Cyclin D1: Difference between revisions

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{{see also|Cyclin D}}
{{see also|Cyclin D}}
{{Infobox_gene}}
{{Infobox_gene}}
'''Cyclin-D1''' is a [[protein]] that in humans is encoded by the ''CCND1'' [[gene]].<ref name="pmid1826542">{{cite journal | vauthors = Motokura T, Bloom T, Kim HG, Jüppner H, Ruderman JV, Kronenberg HM, Arnold A | title = A novel cyclin encoded by a bcl1-linked candidate oncogene | journal = Nature | volume = 350 | issue = 6318 | pages = 512–5 | date = May 1991 | pmid = 1826542 | pmc =  | doi = 10.1038/350512a0 | bibcode = 1991Natur.350..512M }}</ref><ref name="pmid1833066">{{cite journal | vauthors = Lew DJ, Dulić V, Reed SI | title = Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast | journal = Cell | volume = 66 | issue = 6 | pages = 1197–206 | date = October 1991 | pmid = 1833066 | pmc =  | doi = 10.1016/0092-8674(91)90042-W }}</ref>
'''Cyclin D1''' is a [[protein]] that in humans is encoded by the ''CCND1'' [[gene]].<ref name="pmid1826542">{{cite journal | vauthors = Motokura T, Bloom T, Kim HG, Jüppner H, Ruderman JV, Kronenberg HM, Arnold A | title = A novel cyclin encoded by a bcl1-linked candidate oncogene | journal = Nature | volume = 350 | issue = 6318 | pages = 512–5 | date = April 1991 | pmid = 1826542 | pmc =  | doi = 10.1038/350512a0 | bibcode = 1991Natur.350..512M }}</ref><ref name="pmid1833066">{{cite journal | vauthors = Lew DJ, Dulić V, Reed SI | title = Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast | journal = Cell | volume = 66 | issue = 6 | pages = 1197–206 | date = September 1991 | pmid = 1833066 | pmc =  | doi = 10.1016/0092-8674(91)90042-W }}</ref>


== Gene expression ==
== Gene expression ==


The CCND1 gene encodes the cyclin D1 protein.  The human CCNDI gene is located on the long arm of chromosome 11 (band 11q13).  It is 13,388 basepairs long, and translates into 295 amino acids.<ref>{{cite web |url= http://www.genecards.org/cgi-bin/carddisp.pl?gene=CCND1 | title= "CCND1" Gene |date= 2013|website=GeneCards |publisher= "Weizmann Institute of Science" |access-date=May 6, 2015}}</ref> Cyclin D1 is expressed in all adult human tissues with the exception of cells derived from bone marrow stem cell lines (both lymphoid and myeloid).<ref>{{cite journal | vauthors = Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC | title = Characterization of a candidate bcl-1 gene | journal = Molecular and Cellular Biology | volume = 11 | issue = 10 | pages = 4846–53 | date = Oct 1991 | pmid = 1833629 | pmc = 361453 }}</ref><ref>{{cite journal | vauthors = Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ, Look AT | title = Genomic organization, chromosomal localization, and independent expression of human cyclin D genes | journal = Genomics | volume = 13 | issue = 3 | pages = 565–74 | date = Jul 1992 | pmid = 1386335 | doi=10.1016/0888-7543(92)90126-d}}</ref>
The CCND1 gene encodes the cyclin D1 protein.  The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13).  It is 13,388 base pairs long, and translates into 295 amino acids.<ref>{{cite web |url= https://www.genecards.org/cgi-bin/carddisp.pl?gene=CCND1 | title= "CCND1" Gene |date= 2013|website=GeneCards |publisher= "Weizmann Institute of Science" |access-date=May 6, 2015}}</ref> Cyclin D1 is expressed in all adult human tissues with the exception of cells derived from bone marrow stem cell lines (both lymphoid and myeloid).<ref>{{cite journal | vauthors = Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC | title = Characterization of a candidate bcl-1 gene | journal = Molecular and Cellular Biology | volume = 11 | issue = 10 | pages = 4846–53 | date = October 1991 | pmid = 1833629 | pmc = 361453 }}</ref><ref>{{cite journal | vauthors = Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ, Look AT | title = Genomic organization, chromosomal localization, and independent expression of human cyclin D genes | journal = Genomics | volume = 13 | issue = 3 | pages = 565–74 | date = July 1992 | pmid = 1386335 | doi = 10.1016/0888-7543(92)90126-d }}</ref>


== Protein structure ==
== Protein structure ==


Cyclin D1 is composed of the following protein domains and motifs:<ref name="Musgrove">{{cite journal | vauthors = Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL | title = Cyclin D as a therapeutic target in cancer | journal = Nature Reviews. Cancer | volume = 11 | issue = 8 | pages = 558–72 | date = Aug 2011 | pmid = 21734724 | doi = 10.1038/nrc3090 }}</ref><ref name="ReferenceA">{{cite journal | vauthors = Knudsen KE, Diehl JA, Haiman CA, Knudsen ES | title = Cyclin D1: polymorphism, aberrant splicing and cancer risk | journal = Oncogene | volume = 25 | issue = 11 | pages = 1620–8 | date = Mar 2006 | pmid = 16550162 | doi = 10.1038/sj.onc.1209371 }}</ref>
Cyclin D1 is composed of the following protein domains and motifs:<ref name="Musgrove">{{cite journal | vauthors = Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL | title = Cyclin D as a therapeutic target in cancer | journal = Nature Reviews. Cancer | volume = 11 | issue = 8 | pages = 558–72 | date = July 2011 | pmid = 21734724 | doi = 10.1038/nrc3090 }}</ref><ref name="ReferenceA">{{cite journal | vauthors = Knudsen KE, Diehl JA, Haiman CA, Knudsen ES | title = Cyclin D1: polymorphism, aberrant splicing and cancer risk | journal = Oncogene | volume = 25 | issue = 11 | pages = 1620–8 | date = March 2006 | pmid = 16550162 | doi = 10.1038/sj.onc.1209371 }}</ref>
* retinoblastoma protein (pRb) binding motif;
* retinoblastoma protein (pRb) binding motif;
* cyclin box domain for cyclin-dependent kinase (CDK) binding and CDK inhibitor binding;
* cyclin box domain for cyclin-dependent kinase (CDK) binding and CDK inhibitor binding;
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== Function ==
== Function ==


The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Cyclins function as regulators of CDKs ([[Cyclin-dependent kinase]]). Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of [[Cyclin-dependent kinase 4|CDK4]] or [[Cyclin-dependent kinase 6|CDK6]], whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein [[Retinoblastoma protein|Rb]] and the expression of this gene is regulated positively by [[Retinoblastoma protein|Rb]]. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis.<ref name="entrez">{{cite web | title = Entrez Gene: CCND1 cyclin D1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=595| accessdate = }}</ref>
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Cyclins function as regulators of CDKs ([[Cyclin-dependent kinase]]). Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of [[Cyclin-dependent kinase 4|CDK4]] or [[Cyclin-dependent kinase 6|CDK6]], whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein [[Retinoblastoma protein|Rb]] and the expression of this gene is regulated positively by [[Retinoblastoma protein|Rb]]. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis.<ref name="entrez">{{cite web | title = Entrez Gene: CCND1 cyclin D1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=595| access-date = }}</ref>


[[Image:Mantle cell lymphoma - intermed mag - cyclin D1.jpg|thumb|right|125px|[[Micrograph]] of cyclin D1 staining in a [[mantle cell lymphoma]].]]
[[Image:Mantle cell lymphoma - intermed mag - cyclin D1.jpg|thumb|right|125px|[[Micrograph]] of cyclin D1 staining in a [[mantle cell lymphoma]].]]
Immunohistochemical staining of cyclin D1 antibodies is used to diagnose [[mantle cell lymphoma]].
Immunohistochemical staining of cyclin D1 antibodies is used to diagnose [[mantle cell lymphoma]].


Cyclin D1 has been found to be overexpressed in [[breast carcinoma]]. Its potential use as a biomarker was suggested.<ref name=" pmid = 24190141 ">{{cite journal | vauthors = He Y, Liu Z, Qiao C, Xu M, Yu J, Li G | title = Expression and significance of Wnt signaling components and their target genes in breast carcinoma | journal = Mol Med Rep | volume = 9 | issue = 1 | pages = 137–43 | date = Jan 2014 | pmid = 24190141 | doi = 10.3892/mmr.2013.1774 | url = http://www.spandidos-publications.com/mmr/9/1/137 }}</ref>
Cyclin D1 has been found to be overexpressed in [[breast carcinoma]]. Its potential use as a biomarker was suggested.<ref name=" pmid = 24190141 ">{{cite journal | vauthors = He Y, Liu Z, Qiao C, Xu M, Yu J, Li G | title = Expression and significance of Wnt signaling components and their target genes in breast carcinoma | journal = Molecular Medicine Reports | volume = 9 | issue = 1 | pages = 137–43 | date = January 2014 | pmid = 24190141 | doi = 10.3892/mmr.2013.1774 | url = http://www.spandidos-publications.com/mmr/9/1/137 }}</ref>


=== Normal function ===
=== Normal function ===


Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle.<ref name="Baldin">{{cite journal | vauthors = Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G | title = Cyclin D1 is a nuclear protein required for cell cycle progression in G1 | journal = Genes & Development | volume = 7 | issue = 5 | pages = 812–21 | date = May 1993 | pmid = 8491378 | doi=10.1101/gad.7.5.812}}</ref>  During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase.<ref name="Baldin"/>  Cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6. The protein dimerizes with CDK4/6 to regulate the G1/S phase transition and entry into the S-phase.
Cyclin D1 was originally cloned as a breakpoint rearrangement in parathyroid adenoma<ref>{{cite journal | vauthors = Motokura T, Bloom T, Kim HG, Jüppner H, Ruderman JV, Kronenberg HM, Arnold A | title = A novel cyclin encoded by a bcl1-linked candidate oncogene | journal = Nature | volume = 350 | issue = 6318 | pages = 512–5 | date = April 1991 | pmid = 1826542 | doi = 10.1038/350512a0 | bibcode = 1991Natur.350..512M }}</ref> and was shown to be required for progression through the G1 phase of the cell cycle to induce cell migration,<ref>{{cite journal | vauthors = Neumeister P, Pixley FJ, Xiong Y, Xie H, Wu K, Ashton A, Cammer M, Chan A, Symons M, Stanley ER, Pestell RG | title = Cyclin D1 governs adhesion and motility of macrophages | journal = Molecular Biology of the Cell | volume = 14 | issue = 5 | pages = 2005–15 | date = May 2003 | pmid = 12802071 | pmc = 165093 | doi = 10.1091/mbc.02-07-0102 }}</ref> angiogenesis<ref>{{cite journal | vauthors = Holnthoner W, Pillinger M, Groger M, Wolff K, Ashton AW, Albanese C, Neumeister P, Pestell RG, Petzelbauer P | title = Fibroblast growth factor-2 induces Lef/Tcf-dependent transcription in human endothelial cells | journal = The Journal of Biological Chemistry | volume = 277 | issue = 48 | pages = 45847–53 | date = November 2002 | pmid = 12235165 | doi = 10.1074/jbc.M209354200 }}</ref> and to induce the Warburg effect.<ref>{{cite journal | vauthors = Sakamaki T, Casimiro MC, Ju X, Quong AA, Katiyar S, Liu M, Jiao X, Li A, Zhang X, Lu Y, Wang C, Byers S, Nicholson R, Link T, Shemluck M, Yang J, Fricke ST, Novikoff PM, Papanikolaou A, Arnold A, Albanese C, Pestell R | title = Cyclin D1 determines mitochondrial function in vivo | journal = Molecular and Cellular Biology | volume = 26 | issue = 14 | pages = 5449–69 | date = July 2006 | pmid = 16809779 | pmc = 1592725 | doi = 10.1128/MCB.02074-05 }}</ref> Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle.<ref name="Baldin">{{cite journal | vauthors = Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G | title = Cyclin D1 is a nuclear protein required for cell cycle progression in G1 | journal = Genes & Development | volume = 7 | issue = 5 | pages = 812–21 | date = May 1993 | pmid = 8491378 | doi = 10.1101/gad.7.5.812 }}</ref>  During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase.<ref name="Baldin"/>  Cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6. The protein dimerizes with CDK4/6 to regulate the G1/S phase transition and entry into the S-phase.


=== CDK dependent functions ===
=== CDK dependent functions ===


The cyclin D1-CDK4 complex promotes passage through the G1 phase by inhibiting the retinoblastoma protein (pRb).<ref>{{cite journal | vauthors = Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ | title = Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins | journal = Cell | volume = 71 | issue = 2 | pages = 323–34 | date = Oct 1992 | pmid = 1423597 | doi=10.1016/0092-8674(92)90360-o}}</ref>  Cyclin D1-CDK4 inhibits pRb through phosphorylation, allowing E2F transcription factors to transcribe genes required for entry into the S phase.  Inactive pRb allows cell cycle progression through the G1/S transition and allows for DNA synthesis.  Cyclin D1-CDK4 also enables the activation of cyclin E-CDK2 complex by sequestering Cip/Kip family CDK inhibitory proteins p21 and p27, allowing entry into the S phase.<ref name="Diehl">{{cite journal | vauthors = Diehl JA | title = Cycling to cancer with cyclin D1 | journal = Cancer Biology & Therapy | volume = 1 | issue = 3 | pages = 226–31 | year = 2002 | pmid = 12432268 | doi=10.4161/cbt.72}}</ref>
The cyclin D1-CDK4 complex promotes passage through the G1 phase by inhibiting the retinoblastoma protein (pRb).<ref>{{cite journal | vauthors = Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ | title = Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins | journal = Cell | volume = 71 | issue = 2 | pages = 323–34 | date = October 1992 | pmid = 1423597 | doi = 10.1016/0092-8674(92)90360-o }}</ref>  Cyclin D1-CDK4 inhibits pRb through phosphorylation, allowing E2F transcription factors to transcribe genes required for entry into the S phase.  Inactive pRb allows cell cycle progression through the G1/S transition and allows for DNA synthesis.  Cyclin D1-CDK4 also enables the activation of cyclin E-CDK2 complex by sequestering Cip/Kip family CDK inhibitory proteins p21 and p27, allowing entry into the S phase.<ref name="Diehl">{{cite journal | vauthors = Diehl JA | title = Cycling to cancer with cyclin D1 | journal = Cancer Biology & Therapy | volume = 1 | issue = 3 | pages = 226–31 | year = 2002 | pmid = 12432268 | doi = 10.4161/cbt.72 }}</ref>


Cyclin D1-CDK4 also associates with several transcription factors and transcriptional co-regulators.<ref name="Musgrove" />
Cyclin D1-CDK4 also associates with several transcription factors and transcriptional co-regulators.<ref name="Musgrove" />
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=== CDK independent functions ===
=== CDK independent functions ===


Independent of CDK, cyclin D1 binds to nuclear receptors (including estrogen receptor α, thyroid hormone receptor, PPARγ <ref>{{cite journal | vauthors = Wang C, Li Z, Fu M, Bouras T, Pestell RG | title = Signal transduction mediated by cyclin D1: from mitogens to cell proliferation: a molecular target with therapeutic potential | journal = Cancer Treatment and Research | volume = 119 | pages = 217–37 | year = 2004 | pmid = 15164880 | doi=10.1007/1-4020-7847-1_11| series = Cancer Treatment and Research | isbn = 1-4020-7822-6 }}</ref><ref>{{cite journal | vauthors = Zhang JM, Wei Q, Zhao X, Paterson BM | title = Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4 | journal = The EMBO Journal | volume = 18 | issue = 4 | pages = 926–33 | date = Feb 1999 | pmid = 10022835 | pmc = 1171185 | doi = 10.1093/emboj/18.4.926 }}</ref><ref>{{cite journal | vauthors = Horstmann S, Ferrari S, Klempnauer KH | title = Regulation of B-Myb activity by cyclin D1 | journal = Oncogene | volume = 19 | issue = 2 | pages = 298–306 | date = Jan 2000 | pmid = 10645009 | doi = 10.1038/sj.onc.1203302 }}</ref><ref>{{cite journal | vauthors = Inoue K, Sherr CJ | title = Gene expression and cell cycle arrest mediated by transcription factor DMP1 is antagonized by D-type cyclins through a cyclin-dependent-kinase-independent mechanism | journal = Molecular and Cellular Biology | volume = 18 | issue = 3 | pages = 1590–600 | date = Mar 1998 | pmid = 9488476 | pmc = 108874 }}</ref> and AR <ref name="Reutens AT p300">{{cite journal | vauthors = Reutens AT, Fu M, Wang C, Albanese C, McPhaul MJ, Sun Z, Balk SP, Jänne OA, Palvimo JJ, Pestell RG | title = Cyclin D1 binds the androgen receptor and regulates hormone-dependent signaling in a p300/CBP-associated factor (P/CAF)-dependent manner | journal = Molecular Endocrinology | volume = 15 | issue = 5 | pages = 797–811 | date = May 2001 | pmid = 11328859 | doi = 10.1210/mend.15.5.0641 }}</ref>) to regulate cell proliferation, growth, and differentiation. Cyclin D1 also binds to histone acetylases and histone deacetylases to regulate cell proliferation and cell differentiation genes <ref name="Fu" >{{cite journal | vauthors = Fu M, Wang C, Li Z, Sakamaki T, Pestell RG | title = Minireview: Cyclin D1: normal and abnormal functions | journal = Endocrinology | volume = 145 | issue = 12 | pages = 5439–47 | date = Dec 2004 | pmid = 15331580 | doi = 10.1210/en.2004-0959 }}</ref><ref>{{cite journal | vauthors = McMahon C, Suthiphongchai T, DiRenzo J, Ewen ME | title = P/CAF associates with cyclin D1 and potentiates its activation of the estrogen receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 10 | pages = 5382–7 | date = May 1999 | pmid = 10318892 | pmc = 21868 | doi=10.1073/pnas.96.10.5382| bibcode = 1999PNAS...96.5382M }}</ref><ref name="Reutens AT p300"/><ref name = "Fu_2005">{{cite journal | vauthors = Fu M, Rao M, Bouras T, Wang C, Wu K, Zhang X, Li Z, Yao TP, Pestell RG | title = Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment | journal = The Journal of Biological Chemistry | volume = 280 | issue = 17 | pages = 16934–41 | date = Apr 2005 | pmid = 15713663 | doi = 10.1074/jbc.M500403200 }}</ref> in the early to mid-G1 phase.
Independent of CDK, cyclin D1 binds to nuclear receptors (including estrogen receptor α,<ref name="pmid9039267">{{cite journal | vauthors = Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ | title = CDK-independent activation of estrogen receptor by cyclin D1 | journal = Cell | volume = 88 | issue = 3 | pages = 405–15 | date = February 1997 | pmid = 9039267 | doi = 10.1016/S0092-8674(00)81879-6 }}</ref> thyroid hormone receptor, PPARγ <ref>{{Cite book | vauthors = Wang C, Li Z, Fu M, Bouras T, Pestell RG | title = Signal transduction mediated by cyclin D1: from mitogens to cell proliferation: a molecular target with therapeutic potential | volume = 119 | pages = 217–37 | year = 2004 | pmid = 15164880 | doi = 10.1007/1-4020-7847-1_11 | series = Cancer Treatment and Research | isbn = 978-1-4020-7822-4 }}</ref><ref>{{cite journal | vauthors = Fu M, Rao M, Bouras T, Wang C, Wu K, Zhang X, Li Z, Yao TP, Pestell RG | title = Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment | journal = The Journal of Biological Chemistry | volume = 280 | issue = 17 | pages = 16934–41 | date = April 2005 | pmid = 15713663 | doi = 10.1074/jbc.m500403200 | department = primary }}</ref> and AR<ref name="Reutens AT p300">{{cite journal | vauthors = Reutens AT, Fu M, Wang C, Albanese C, McPhaul MJ, Sun Z, Balk SP, Jänne OA, Palvimo JJ, Pestell RG | title = Cyclin D1 binds the androgen receptor and regulates hormone-dependent signaling in a p300/CBP-associated factor (P/CAF)-dependent manner | journal = Molecular Endocrinology | volume = 15 | issue = 5 | pages = 797–811 | date = May 2001 | pmid = 11328859 | doi = 10.1210/mend.15.5.0641 }}</ref> ) to regulate cell proliferation, growth, and differentiation. Cyclin D1 also binds to histone acetylases and histone deacetylases to regulate cell proliferation and cell differentiation genes <ref name="Fu" >{{cite journal | vauthors = Fu M, Wang C, Li Z, Sakamaki T, Pestell RG | title = Minireview: Cyclin D1: normal and abnormal functions | journal = Endocrinology | volume = 145 | issue = 12 | pages = 5439–47 | date = December 2004 | pmid = 15331580 | doi = 10.1210/en.2004-0959 }}</ref><ref>{{cite journal | vauthors = McMahon C, Suthiphongchai T, DiRenzo J, Ewen ME | title = P/CAF associates with cyclin D1 and potentiates its activation of the estrogen receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 10 | pages = 5382–7 | date = May 1999 | pmid = 10318892 | pmc = 21868 | doi = 10.1073/pnas.96.10.5382 | bibcode = 1999PNAS...96.5382M }}</ref><ref name="Reutens AT p300"/><ref name = "Fu_2005">{{cite journal | vauthors = Fu M, Rao M, Bouras T, Wang C, Wu K, Zhang X, Li Z, Yao TP, Pestell RG | title = Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment | journal = The Journal of Biological Chemistry | volume = 280 | issue = 17 | pages = 16934–41 | date = April 2005 | pmid = 15713663 | doi = 10.1074/jbc.M500403200 }}</ref> in the early to mid-G1 phase.


== Synthesis and degradation ==
== Synthesis and degradation ==


Increasing cyclin D1 levels during the G1 phase is induced by mitogenic growth factors <ref>{{cite journal | vauthors = Böhmer RM, Scharf E, Assoian RK | title = Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin D1 | journal = Molecular Biology of the Cell | volume = 7 | issue = 1 | pages = 101–111 | date = Jan 1996 | pmid = 8741843 | pmc = 278616 | doi=10.1091/mbc.7.1.101}}</ref> primarily through Ras mediated pathways,<ref>{{cite journal | vauthors = Mittnacht S, Paterson H, Olson MF, Marshall CJ | title = Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein | journal = Current Biology | volume = 7 | issue = 3 | pages = 219–21 | date = Mar 1997 | pmid = 9395436 | doi=10.1016/s0960-9822(97)70094-0}}</ref><ref>{{cite journal | vauthors = Mulcahy LS, Smith MR, Stacey DW | title = Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells | journal = Nature | volume = 313 | issue = 5999 | pages = 241–3 | year = 1985 | pmid = 3918269 | doi=10.1038/313241a0| bibcode = 1985Natur.313..241M }}</ref><ref>{{cite journal | vauthors = Peeper DS, Upton TM, Ladha MH, Neuman E, Zalvide J, Bernards R, DeCaprio JA, Ewen ME | title = Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein | journal = Nature | volume = 386 | issue = 6621 | pages = 177–81 | date = Mar 1997 | pmid = 9062190 | doi = 10.1038/386177a0 | bibcode = 1997Natur.386..177P }}</ref> and hormones.<ref name="Fu" /> These Ras-mediated pathways lead to the increase in transcription of cyclin D1, and inhibit its proteolysis and export from the nucleus.<ref name="Alao">{{cite journal | vauthors = Alao JP | title = The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention | journal = Molecular Cancer | volume = 6 | pages = 24 | year = 2007 | pmid = 17407548 | pmc = 1851974 | doi = 10.1186/1476-4598-6-24 }}</ref>  
Increasing cyclin D1 levels during the G1 phase is induced by mitogenic growth factors <ref>{{cite journal | vauthors = Böhmer RM, Scharf E, Assoian RK | title = Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin D1 | journal = Molecular Biology of the Cell | volume = 7 | issue = 1 | pages = 101–111 | date = January 1996 | pmid = 8741843 | pmc = 278616 | doi = 10.1091/mbc.7.1.101 }}</ref> primarily through Ras mediated pathways,<ref>{{cite journal | vauthors = Mittnacht S, Paterson H, Olson MF, Marshall CJ | title = Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein | journal = Current Biology | volume = 7 | issue = 3 | pages = 219–21 | date = March 1997 | pmid = 9395436 | doi = 10.1016/s0960-9822(97)70094-0 }}</ref><ref>{{cite journal | vauthors = Mulcahy LS, Smith MR, Stacey DW | title = Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells | journal = Nature | volume = 313 | issue = 5999 | pages = 241–3 | year = 1985 | pmid = 3918269 | doi = 10.1038/313241a0 | bibcode = 1985Natur.313..241M }}</ref><ref>{{cite journal | vauthors = Peeper DS, Upton TM, Ladha MH, Neuman E, Zalvide J, Bernards R, DeCaprio JA, Ewen ME | title = Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein | journal = Nature | volume = 386 | issue = 6621 | pages = 177–81 | date = March 1997 | pmid = 9062190 | doi = 10.1038/386177a0 | bibcode = 1997Natur.386..177P | url = http://dspace.library.uu.nl/handle/1874/15252 | format = Submitted manuscript }}</ref> and hormones.<ref name="Fu" /> These Ras-mediated pathways lead to the increase in transcription of cyclin D1, and inhibit its proteolysis and export from the nucleus.<ref name="Alao">{{cite journal | vauthors = Alao JP | title = The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention | journal = Molecular Cancer | volume = 6 | pages = 24 | date = April 2007 | pmid = 17407548 | pmc = 1851974 | doi = 10.1186/1476-4598-6-24 }}</ref>  
Cyclin D1 is degraded via an ubiquitin-mediated proteolysis pathway at the end of the S-phase.  Phosphorylation of cyclin D1’s threonine residue T286 marks the protein for export from the nucleus and proteolytic degradation.<ref name = "a12460907">{{cite journal | vauthors = Hui R, Finney GL, Carroll JS, Lee CS, Musgrove EA, Sutherland RL | title = Constitutive overexpression of cyclin D1 but not cyclin E confers acute resistance to antiestrogens in T-47D breast cancer cells | journal = Cancer Research | volume = 62 | issue = 23 | pages = 6916–23 | date = Dec 2002 | pmid = 12460907 }}</ref>
Cyclin D1 is degraded via an ubiquitin-mediated proteolysis pathway at the end of the S-phase.  Phosphorylation of cyclin D1’s threonine residue T286 marks the protein for export from the nucleus and proteolytic degradation.<ref name = "a12460907">{{cite journal | vauthors = Hui R, Finney GL, Carroll JS, Lee CS, Musgrove EA, Sutherland RL | title = Constitutive overexpression of cyclin D1 but not cyclin E confers acute resistance to antiestrogens in T-47D breast cancer cells | journal = Cancer Research | volume = 62 | issue = 23 | pages = 6916–23 | date = December 2002 | pmid = 12460907 }}</ref>


== Clinical significance ==
== Clinical significance ==
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* amplification of the CCND1 gene / overexpression of cyclin D1;
* amplification of the CCND1 gene / overexpression of cyclin D1;
* chromosomal translocation of the CCND1 gene;
* chromosomal translocation of the CCND1 gene;
* disruption of nuclear export <ref>{{cite journal | vauthors = Alt JR, Cleveland JL, Hannink M, Diehl JA | title = Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation | journal = Genes & Development | volume = 14 | issue = 24 | pages = 3102–14 | date = Dec 2000 | pmid = 11124803 | pmc = 317128 | doi=10.1101/gad.854900}}</ref> and proteolysis of cyclin D1<ref>{{cite journal | vauthors = Diehl JA, Zindy F, Sherr CJ | title = Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway | journal = Genes & Development | volume = 11 | issue = 8 | pages = 957–72 | date = Apr 1997 | pmid = 9136925 | doi=10.1101/gad.11.8.957}}</ref>
* disruption of nuclear export <ref>{{cite journal | vauthors = Alt JR, Cleveland JL, Hannink M, Diehl JA | title = Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation | journal = Genes & Development | volume = 14 | issue = 24 | pages = 3102–14 | date = December 2000 | pmid = 11124803 | pmc = 317128 | doi = 10.1101/gad.854900 }}</ref> and proteolysis of cyclin D1<ref>{{cite journal | vauthors = Diehl JA, Zindy F, Sherr CJ | title = Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway | journal = Genes & Development | volume = 11 | issue = 8 | pages = 957–72 | date = April 1997 | pmid = 9136925 | doi = 10.1101/gad.11.8.957 }}</ref>
*induction of transcription by oncogenic Ras, Src, ErbB2 and STATs;<ref>{{cite journal|last1=Casimiro|first1=M|last2=Rodriguez|first2=O|last3=Pootrakul|first3=L|last4=Aventian|first4=M|last5=Lushina|first5=N|last6=Cromelin|first6=C|last7=Ferzli|first7=G|last8=Johnson|first8=K|last9=Fricke|first9=S|last10=Diba|first10=F|last11=Kallakury|first11=B|last12=Ohanyerenwa|first12=C|last13=Chen|first13=M|last14=Ostrowski|first14=M|last15=Hung|first15=MC|last16=Rabbani|first16=SA|last17=Datar|first17=R|last18=Cote|first18=R|last19=Pestell|first19=R|last20=Albanese|first20=C|title=ErbB-2 induces the cyclin D1 gene in prostate epithelial cells in vitro and in vivo.|journal=Cancer Research|date=1 May 2007|volume=67|issue=9|pages=4364–72|pmid=17483350|doi=10.1158/0008-5472.CAN-06-1898}}</ref><ref>{{cite journal|last1=Amanatullah|first1=DF|last2=Zafonte|first2=BT|last3=Albanese|first3=C|last4=Fu|first4=M|last5=Messiers|first5=C|last6=Hassell|first6=J|last7=Pestell|first7=RG|title=Ras regulation of cyclin D1 promoter.|journal=Methods in Enzymology|date=2001|volume=333|pages=116–27|pmid=11400329}}</ref><ref>{{cite journal|last1=Matsumura|first1=I|last2=Kitamura|first2=T|last3=Wakao|first3=H|last4=Tanaka|first4=H|last5=Hashimoto|first5=K|last6=Albanese|first6=C|last7=Downward|first7=J|last8=Pestell|first8=RG|last9=Kanakura|first9=Y|title=Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine-dependent growth of hematopoietic cells.|journal=The EMBO Journal|date=1 March 1999|volume=18|issue=5|pages=1367–77|pmid=10064602|doi=10.1093/emboj/18.5.1367|pmc=1171226}}</ref><ref>{{cite journal|pmid=7559524 | volume=270 | title=Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions | journal=J Biol Chem | pages=23589–97 | vauthors=Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG}}</ref>
*induction of transcription by oncogenic Ras, Src, ErbB2 and STATs;<ref>{{cite journal | vauthors = Casimiro M, Rodriguez O, Pootrakul L, Aventian M, Lushina N, Cromelin C, Ferzli G, Johnson K, Fricke S, Diba F, Kallakury B, Ohanyerenwa C, Chen M, Ostrowski M, Hung MC, Rabbani SA, Datar R, Cote R, Pestell R, Albanese C | title = ErbB-2 induces the cyclin D1 gene in prostate epithelial cells in vitro and in vivo | journal = Cancer Research | volume = 67 | issue = 9 | pages = 4364–72 | date = May 2007 | pmid = 17483350 | doi = 10.1158/0008-5472.CAN-06-1898 }}</ref><ref>{{Cite book | vauthors = Amanatullah DF, Zafonte BT, Albanese C, Fu M, Messiers C, Hassell J, Pestell RG | title = Ras regulation of cyclin D1 promoter | journal = Methods in Enzymology | volume = 333 | pages = 116–27 | date = 2001 | pmid = 11400329 | doi = 10.1016/s0076-6879(01)33050-1 | isbn = 9780121822347 }}</ref><ref>{{cite journal | vauthors = Matsumura I, Kitamura T, Wakao H, Tanaka H, Hashimoto K, Albanese C, Downward J, Pestell RG, Kanakura Y | title = Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine-dependent growth of hematopoietic cells | journal = The EMBO Journal | volume = 18 | issue = 5 | pages = 1367–77 | date = March 1999 | pmid = 10064602 | pmc = 1171226 | doi = 10.1093/emboj/18.5.1367 }}</ref><ref>{{cite journal | vauthors = Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG | title = Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions | journal = The Journal of Biological Chemistry | volume = 270 | issue = 40 | pages = 23589–97 | date = October 1995 | pmid = 7559524 | doi = 10.1074/jbc.270.40.23589 }}</ref>


Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis.<ref>{{cite journal | vauthors = Jares P, Colomer D, Campo E | title = Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics | journal = Nature Reviews. Cancer | volume = 7 | issue = 10 | pages = 750–62 | date = Oct 2007 | pmid = 17891190 | doi = 10.1038/nrc2230 }}</ref><ref>{{cite journal | vauthors = Thomas GR, Nadiminti H, Regalado J | title = Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma | journal = International Journal of Experimental Pathology | volume = 86 | issue = 6 | pages = 347–63 | date = Dec 2005 | pmid = 16309541 | pmc = 2517451 | doi = 10.1111/j.0959-9673.2005.00447.x }}</ref> Amplification of the CCND1 gene is present in:
Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis.<ref>{{cite journal | vauthors = Jares P, Colomer D, Campo E | title = Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics | journal = Nature Reviews. Cancer | volume = 7 | issue = 10 | pages = 750–62 | date = October 2007 | pmid = 17891190 | doi = 10.1038/nrc2230 }}</ref><ref>{{cite journal | vauthors = Thomas GR, Nadiminti H, Regalado J | title = Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma | journal = International Journal of Experimental Pathology | volume = 86 | issue = 6 | pages = 347–63 | date = December 2005 | pmid = 16309541 | pmc = 2517451 | doi = 10.1111/j.0959-9673.2005.00447.x }}</ref> Amplification of the CCND1 gene is present in:
* non-small cell lung cancers (30-46%) <ref>{{cite journal | vauthors = Jin M, Inoue S, Umemura T, Moriya J, Arakawa M, Nagashima K, Kato H | title = Cyclin D1, p16 and retinoblastoma gene product expression as a predictor for prognosis in non-small cell lung cancer at stages I and II | journal = Lung Cancer | volume = 34 | issue = 2 | pages = 207–18 | date = Nov 2001 | pmid = 11679179 | doi=10.1016/s0169-5002(01)00225-2}}</ref><ref>{{cite journal | vauthors = Yamanouchi H, Furihata M, Fujita J, Murakami H, Yoshinouchi T, Takahara J, Ohtsuki Y | title = Expression of cyclin E and cyclin D1 in non-small cell lung cancers | journal = Lung Cancer | volume = 31 | issue = 1 | pages = 3–8 | date = Jan 2001 | pmid = 11162860 | doi=10.1016/s0169-5002(00)00160-4}}</ref>
* non-small cell lung cancers (30-46%) <ref>{{cite journal | vauthors = Jin M, Inoue S, Umemura T, Moriya J, Arakawa M, Nagashima K, Kato H | title = Cyclin D1, p16 and retinoblastoma gene product expression as a predictor for prognosis in non-small cell lung cancer at stages I and II | journal = Lung Cancer | volume = 34 | issue = 2 | pages = 207–18 | date = November 2001 | pmid = 11679179 | doi = 10.1016/s0169-5002(01)00225-2 }}</ref><ref>{{cite journal | vauthors = Yamanouchi H, Furihata M, Fujita J, Murakami H, Yoshinouchi T, Takahara J, Ohtsuki Y | title = Expression of cyclin E and cyclin D1 in non-small cell lung cancers | journal = Lung Cancer | volume = 31 | issue = 1 | pages = 3–8 | date = January 2001 | pmid = 11162860 | doi = 10.1016/s0169-5002(00)00160-4 }}</ref>
* head and neck squamous cell carcinomas (30-50%) <ref>{{cite journal | vauthors = Ikeguchi M, Sakatani T, Ueta T, Kaibara N | title = Cyclin D1 expression and retinoblastoma gene protein (pRB) expression in esophageal squamous cell carcinoma | journal = Journal of Cancer Research and Clinical Oncology | volume = 127 | issue = 9 | pages = 531–6 | date = Sep 2001 | pmid = 11570573 | doi=10.1007/s004320100265}}</ref><ref>{{cite journal | vauthors = Izzo JG, Papadimitrakopoulou VA, Li XQ, Ibarguen H, Lee JS, Ro JY, El-Naggar A, Hong WK, Hittelman WN | title = Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification | journal = Oncogene | volume = 17 | issue = 18 | pages = 2313–22 | date = Nov 1998 | pmid = 9811462 | doi = 10.1038/sj.onc.1202153 }}</ref><ref>{{cite journal | vauthors = Bartkova J, Lukas J, Müller H, Strauss M, Gusterson B, Bartek J | title = Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer | journal = Cancer Research | volume = 55 | issue = 4 | pages = 949–56 | date = Feb 1995 | pmid = 7850812 }}</ref>
* head and neck squamous cell carcinomas (30-50%) <ref>{{cite journal | vauthors = Ikeguchi M, Sakatani T, Ueta T, Kaibara N | title = Cyclin D1 expression and retinoblastoma gene protein (pRB) expression in esophageal squamous cell carcinoma | journal = Journal of Cancer Research and Clinical Oncology | volume = 127 | issue = 9 | pages = 531–6 | date = September 2001 | pmid = 11570573 | doi = 10.1007/s004320100265 }}</ref><ref>{{cite journal | vauthors = Izzo JG, Papadimitrakopoulou VA, Li XQ, Ibarguen H, Lee JS, Ro JY, El-Naggar A, Hong WK, Hittelman WN | title = Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification | journal = Oncogene | volume = 17 | issue = 18 | pages = 2313–22 | date = November 1998 | pmid = 9811462 | doi = 10.1038/sj.onc.1202153 }}</ref><ref>{{cite journal | vauthors = Bartkova J, Lukas J, Müller H, Strauss M, Gusterson B, Bartek J | title = Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer | journal = Cancer Research | volume = 55 | issue = 4 | pages = 949–56 | date = February 1995 | pmid = 7850812 }}</ref>
* pancreatic carcinomas (25%) <ref>{{cite journal | vauthors = Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N, Beger HG | title = Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis | journal = Cancer Research | volume = 57 | issue = 9 | pages = 1634–7 | date = May 1997 | pmid = 9134998 }}</ref>  
* pancreatic carcinomas (25%) <ref>{{cite journal | vauthors = Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N, Beger HG | title = Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis | journal = Cancer Research | volume = 57 | issue = 9 | pages = 1634–7 | date = May 1997 | pmid = 9134998 }}</ref>  
* bladder cancer (15%) <ref>{{cite journal | vauthors = Hall M, Peters G | title = Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer | journal = Advances in Cancer Research | volume = 68 | pages = 67–108 | year = 1996 | pmid = 8712071 | doi=10.1016/s0065-230x(08)60352-8| series = Advances in Cancer Research | isbn = 9780120066681 }}</ref>
* bladder cancer (15%) <ref>{{Cite book | vauthors = Hall M, Peters G | title = Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer | volume = 68 | pages = 67–108 | year = 1996 | pmid = 8712071 | doi = 10.1016/s0065-230x(08)60352-8 | isbn = 9780120066681 | series = Advances in Cancer Research }}</ref>
* pituitary adenomas (49-54%) <ref>{{cite journal | vauthors = Simpson DJ, Frost SJ, Bicknell JE, Broome JC, McNicol AM, Clayton RN, Farrell WE | title = Aberrant expression of G(1)/S regulators is a frequent event in sporadic pituitary adenomas | journal = Carcinogenesis | volume = 22 | issue = 8 | pages = 1149–54 | date = Aug 2001 | pmid = 11470742 | doi=10.1093/carcin/22.8.1149}}</ref><ref>{{cite journal | vauthors = Hibberts NA, Simpson DJ, Bicknell JE, Broome JC, Hoban PR, Clayton RN, Farrell WE | title = Analysis of cyclin D1 (CCND1) allelic imbalance and overexpression in sporadic human pituitary tumors | journal = Clinical Cancer Research | volume = 5 | issue = 8 | pages = 2133–9 | date = Aug 1999 | pmid = 10473097 }}</ref>
* pituitary adenomas (49-54%) <ref>{{cite journal | vauthors = Simpson DJ, Frost SJ, Bicknell JE, Broome JC, McNicol AM, Clayton RN, Farrell WE | title = Aberrant expression of G(1)/S regulators is a frequent event in sporadic pituitary adenomas | journal = Carcinogenesis | volume = 22 | issue = 8 | pages = 1149–54 | date = August 2001 | pmid = 11470742 | doi = 10.1093/carcin/22.8.1149 }}</ref><ref>{{cite journal | vauthors = Hibberts NA, Simpson DJ, Bicknell JE, Broome JC, Hoban PR, Clayton RN, Farrell WE | title = Analysis of cyclin D1 (CCND1) allelic imbalance and overexpression in sporadic human pituitary tumors | journal = Clinical Cancer Research | volume = 5 | issue = 8 | pages = 2133–9 | date = August 1999 | pmid = 10473097 }}</ref>
* breast carcinoma (13%) <ref>{{cite journal | vauthors = Barnes DM, Gillett CE | title = Cyclin D1 in breast cancer | journal = Breast Cancer Research and Treatment | volume = 52 | issue = 1–3 | pages = 1–15 | year = 1998 | pmid = 10066068 | doi=10.1023/a:1006103831990}}</ref><ref>{{cite journal | vauthors = Fantl V, Smith R, Brookes S, Dickson C, Peters G | title = Chromosome 11q13 abnormalities in human breast cancer | journal = Cancer Surveys | volume = 18 | pages = 77–94 | year = 1993 | pmid = 8013002 }}</ref><ref name="a15961768">{{cite journal | vauthors = Arnold A, Papanikolaou A | title = Cyclin D1 in breast cancer pathogenesis | journal = Journal of Clinical Oncology | volume = 23 | issue = 18 | pages = 4215–24 | date = Jun 2005 | pmid = 15961768 | doi = 10.1200/JCO.2005.05.064 }}</ref>
* breast carcinoma (13%) <ref>{{cite journal | vauthors = Barnes DM, Gillett CE | title = Cyclin D1 in breast cancer | journal = Breast Cancer Research and Treatment | volume = 52 | issue = 1–3 | pages = 1–15 | year = 1998 | pmid = 10066068 | doi = 10.1023/a:1006103831990 }}</ref><ref>{{cite journal | vauthors = Fantl V, Smith R, Brookes S, Dickson C, Peters G | title = Chromosome 11q13 abnormalities in human breast cancer | journal = Cancer Surveys | volume = 18 | pages = 77–94 | year = 1993 | pmid = 8013002 }}</ref><ref name="a15961768">{{cite journal | vauthors = Arnold A, Papanikolaou A | title = Cyclin D1 in breast cancer pathogenesis | journal = Journal of Clinical Oncology | volume = 23 | issue = 18 | pages = 4215–24 | date = June 2005 | pmid = 15961768 | doi = 10.1200/JCO.2005.05.064 }}</ref>


Cyclin D1 overexpression is strongly correlated to ER+ breast cancer<ref name="a15961768" /> and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer.<ref name = "a12460907" /><ref>{{cite journal | vauthors = Hodges LC, Cook JD, Lobenhofer EK, Li L, Bennett L, Bushel PR, Aldaz CM, Afshari CA, Walker CL | title = Tamoxifen functions as a molecular agonist inducing cell cycle-associated genes in breast cancer cells | journal = Molecular Cancer Research | volume = 1 | issue = 4 | pages = 300–11 | date = Feb 2003 | pmid = 12612058 }}</ref><ref>{{cite journal | vauthors = Kenny FS, Hui R, Musgrove EA, Gee JM, Blamey RW, Nicholson RI, Sutherland RL, Robertson JF | title = Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer | journal = Clinical Cancer Research | volume = 5 | issue = 8 | pages = 2069–76 | date = Aug 1999 | pmid = 10473088 }}</ref> Overexpression of Cyclin D1b, an isoform, is also present in breast and prostate cancers.<ref name="ReferenceA"/>
Cyclin D1 overexpression is strongly correlated to ER+ breast cancer<ref name="a15961768" /> and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer.<ref name = "a12460907" /><ref>{{cite journal | vauthors = Hodges LC, Cook JD, Lobenhofer EK, Li L, Bennett L, Bushel PR, Aldaz CM, Afshari CA, Walker CL | title = Tamoxifen functions as a molecular agonist inducing cell cycle-associated genes in breast cancer cells | journal = Molecular Cancer Research | volume = 1 | issue = 4 | pages = 300–11 | date = February 2003 | pmid = 12612058 }}</ref><ref>{{cite journal | vauthors = Kenny FS, Hui R, Musgrove EA, Gee JM, Blamey RW, Nicholson RI, Sutherland RL, Robertson JF | title = Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer | journal = Clinical Cancer Research | volume = 5 | issue = 8 | pages = 2069–76 | date = August 1999 | pmid = 10473088 }}</ref> Overexpression of Cyclin D1b, an isoform, is also present in breast and prostate cancers.<ref name="ReferenceA"/>


Chromosomal translocation around the cyclin D1 gene locus is often seen in B mantle cell lymphoma. In mantle cell lymphoma, cyclin D1 is translocated to the IgH promoter<ref>{{cite journal | vauthors = Amin HM, McDonnell TJ, Medeiros LJ, Rassidakis GZ, Leventaki V, O'Connor SL, Keating MJ, Lai R | title = Characterization of 4 mantle cell lymphoma cell lines | journal = Archives of Pathology & Laboratory Medicine | volume = 127 | issue = 4 | pages = 424–31 | date = Apr 2003 | pmid = 12683869 | doi = 10.1043/0003-9985(2003)127<0424:COMCLC>2.0.CO;2 | doi-broken-date = 2017-01-16 }}</ref> leading to cyclin D1 overexpression.  Chromosomal translocation of the cyclin D1 gene locus is also observed in 15 – 20% of multiple myelomas.<ref>{{cite journal | vauthors = Bergsagel PL, Kuehl WM | title = Chromosome translocations in multiple myeloma | journal = Oncogene | volume = 20 | issue = 40 | pages = 5611–22 | date = Sep 2001 | pmid = 11607813 | doi = 10.1038/sj.onc.1204641 }}</ref><ref>{{cite journal | vauthors = Specht K, Haralambieva E, Bink K, Kremer M, Mandl-Weber S, Koch I, Tomer R, Hofler H, Schuuring E, Kluin PM, Fend F, Quintanilla-Martinez L | title = Different mechanisms of cyclin D1 overexpression in multiple myeloma revealed by fluorescence in situ hybridization and quantitative analysis of mRNA levels | journal = Blood | volume = 104 | issue = 4 | pages = 1120–6 | date = Aug 2004 | pmid = 15090460 | doi = 10.1182/blood-2003-11-3837 }}</ref>
Chromosomal translocation around the cyclin D1 gene locus is often seen in B mantle cell lymphoma. In mantle cell lymphoma, cyclin D1 is translocated to the IgH promoter<ref>{{cite journal | vauthors = Amin HM, McDonnell TJ, Medeiros LJ, Rassidakis GZ, Leventaki V, O'Connor SL, Keating MJ, Lai R | title = Characterization of 4 mantle cell lymphoma cell lines | journal = Archives of Pathology & Laboratory Medicine | volume = 127 | issue = 4 | pages = 424–31 | date = April 2003 | pmid = 12683869 | doi = 10.1043/0003-9985(2003)127<0424:COMCLC>2.0.CO;2 | doi-broken-date = 2018-09-10 }}</ref> leading to cyclin D1 overexpression.  Chromosomal translocation of the cyclin D1 gene locus is also observed in 15 – 20% of multiple myelomas.<ref>{{cite journal | vauthors = Bergsagel PL, Kuehl WM | title = Chromosome translocations in multiple myeloma | journal = Oncogene | volume = 20 | issue = 40 | pages = 5611–22 | date = September 2001 | pmid = 11607813 | doi = 10.1038/sj.onc.1204641 }}</ref><ref>{{cite journal | vauthors = Specht K, Haralambieva E, Bink K, Kremer M, Mandl-Weber S, Koch I, Tomer R, Hofler H, Schuuring E, Kluin PM, Fend F, Quintanilla-Martinez L | title = Different mechanisms of cyclin D1 overexpression in multiple myeloma revealed by fluorescence in situ hybridization and quantitative analysis of mRNA levels | journal = Blood | volume = 104 | issue = 4 | pages = 1120–6 | date = August 2004 | pmid = 15090460 | doi = 10.1182/blood-2003-11-3837 }}</ref>


=== Therapeutic target in cancer ===
=== Therapeutic target in cancer ===
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| Inhibition of cyclin D1
| Inhibition of cyclin D1
| Inhibiting translation of cyclin D1 mRNA via mTOR inhibitors <ref>{{cite journal | vauthors = Musgrove EA | title = Cyclins: roles in mitogenic signaling and oncogenic transformation | journal = Growth Factors | volume = 24 | issue = 1 | pages = 13–9 | date = Mar 2006 | pmid = 16393691 | doi = 10.1080/08977190500361812 }}</ref> and  RXR activators.<ref>{{cite journal | vauthors = Dragnev KH, Petty WJ, Shah S, Biddle A, Desai NB, Memoli V, Rigas JR, Dmitrovsky E | title = Bexarotene and erlotinib for aerodigestive tract cancer | journal = Journal of Clinical Oncology | volume = 23 | issue = 34 | pages = 8757–64 | date = Dec 2005 | pmid = 16314636 | doi = 10.1200/JCO.2005.01.9521 }}</ref><ref>{{cite journal | vauthors = Kim ES, Lee JJ, Wistuba II | title = Cotargeting cyclin D1 starts a new chapter in lung cancer prevention and therapy | journal = Cancer Prevention Research | volume = 4 | issue = 6 | pages = 779–82 | date = Jun 2011 | pmid = 21636543 | doi = 10.1158/1940-6207.CAPR-11-0143 }}</ref>  
| Inhibiting translation of cyclin D1 mRNA via mTOR inhibitors <ref>{{cite journal | vauthors = Musgrove EA | title = Cyclins: roles in mitogenic signaling and oncogenic transformation | journal = Growth Factors | volume = 24 | issue = 1 | pages = 13–9 | date = March 2006 | pmid = 16393691 | doi = 10.1080/08977190500361812 }}</ref> and  RXR activators.<ref>{{cite journal | vauthors = Dragnev KH, Petty WJ, Shah S, Biddle A, Desai NB, Memoli V, Rigas JR, Dmitrovsky E | title = Bexarotene and erlotinib for aerodigestive tract cancer | journal = Journal of Clinical Oncology | volume = 23 | issue = 34 | pages = 8757–64 | date = December 2005 | pmid = 16314636 | doi = 10.1200/JCO.2005.01.9521 }}</ref><ref>{{cite journal | vauthors = Kim ES, Lee JJ, Wistuba II | title = Cotargeting cyclin D1 starts a new chapter in lung cancer prevention and therapy | journal = Cancer Prevention Research | volume = 4 | issue = 6 | pages = 779–82 | date = June 2011 | pmid = 21636543 | doi = 10.1158/1940-6207.CAPR-11-0143 }}</ref>  
|-  
|-  
| Inducing Cyclin D1 degradation <ref name="Alao" />
| Inducing Cyclin D1 degradation <ref name="Alao" />
| Retinoid mediated cyclin D1 degradation via the ubiquitin proteolytic pathway;<ref>{{cite journal | vauthors = Boyle JO, Langenfeld J, Lonardo F, Sekula D, Reczek P, Rusch V, Dawson MI, Dmitrovsky E | title = Cyclin D1 proteolysis: a retinoid chemoprevention signal in normal, immortalized, and transformed human bronchial epithelial cells | journal = Journal of the National Cancer Institute | volume = 91 | issue = 4 | pages = 373–9 | date = Feb 1999 | pmid = 10050872 | doi = 10.1093/jnci/91.4.373}}</ref> Differentiation-inducing factor-1 (DIF-1) induced ubiquitin-dependent degradation;<ref>{{cite journal | vauthors = Mori J, Takahashi-Yanaga F, Miwa Y, Watanabe Y, Hirata M, Morimoto S, Shirasuna K, Sasaguri T | title = Differentiation-inducing factor-1 induces cyclin D1 degradation through the phosphorylation of Thr286 in squamous cell carcinoma | journal = Experimental Cell Research | volume = 310 | issue = 2 | pages = 426–33 | date = Nov 2005 | pmid = 16153639 | doi = 10.1016/j.yexcr.2005.07.024 }}</ref> Inhibition of cyclin D1 protein synthesis <ref>{{cite journal | vauthors = Baliga BS, Pronczuk AW, Munro HN | title = Mechanism of cycloheximide inhibition of protein synthesis in a cell-free system prepared from rat liver | journal = The Journal of Biological Chemistry | volume = 244 | issue = 16 | pages = 4480–9 | date = Aug 1969 | pmid = 5806588 }}</ref><ref>{{cite journal | vauthors = Obrig TG, Culp WJ, McKeehan WL, Hardesty B | title = The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes | journal = The Journal of Biological Chemistry | volume = 246 | issue = 1 | pages = 174–81 | date = Jan 1971 | pmid = 5541758 }}</ref>
| Retinoid mediated cyclin D1 degradation via the ubiquitin proteolytic pathway;<ref>{{cite journal | vauthors = Boyle JO, Langenfeld J, Lonardo F, Sekula D, Reczek P, Rusch V, Dawson MI, Dmitrovsky E | title = Cyclin D1 proteolysis: a retinoid chemoprevention signal in normal, immortalized, and transformed human bronchial epithelial cells | journal = Journal of the National Cancer Institute | volume = 91 | issue = 4 | pages = 373–9 | date = February 1999 | pmid = 10050872 | doi = 10.1093/jnci/91.4.373 }}</ref> Differentiation-inducing factor-1 (DIF-1) induced ubiquitin-dependent degradation;<ref>{{cite journal | vauthors = Mori J, Takahashi-Yanaga F, Miwa Y, Watanabe Y, Hirata M, Morimoto S, Shirasuna K, Sasaguri T | title = Differentiation-inducing factor-1 induces cyclin D1 degradation through the phosphorylation of Thr286 in squamous cell carcinoma | journal = Experimental Cell Research | volume = 310 | issue = 2 | pages = 426–33 | date = November 2005 | pmid = 16153639 | doi = 10.1016/j.yexcr.2005.07.024 }}</ref> Inhibition of cyclin D1 protein synthesis <ref>{{cite journal | vauthors = Baliga BS, Pronczuk AW, Munro HN | title = Mechanism of cycloheximide inhibition of protein synthesis in a cell-free system prepared from rat liver | journal = The Journal of Biological Chemistry | volume = 244 | issue = 16 | pages = 4480–9 | date = August 1969 | pmid = 5806588 }}</ref><ref>{{cite journal | vauthors = Obrig TG, Culp WJ, McKeehan WL, Hardesty B | title = The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes | journal = The Journal of Biological Chemistry | volume = 246 | issue = 1 | pages = 174–81 | date = January 1971 | pmid = 5541758 }}</ref>
|-  
|-  
| Inducing nuclear export of Cyclin D1
| Inducing nuclear export of Cyclin D1
| Histone deacetylase inhibitors (HDACIs) to induce nuclear export of Cyclin D1 <ref>{{cite journal | vauthors = Vigushin DM, Coombes RC | title = Histone deacetylase inhibitors in cancer treatment | journal = Anti-Cancer Drugs | volume = 13 | issue = 1 | pages = 1–13 | date = Jan 2002 | pmid = 11914636 | doi=10.1097/00001813-200201000-00001}}</ref>
| Histone deacetylase inhibitors (HDACIs) to induce nuclear export of Cyclin D1 <ref>{{cite journal | vauthors = Vigushin DM, Coombes RC | title = Histone deacetylase inhibitors in cancer treatment | journal = Anti-Cancer Drugs | volume = 13 | issue = 1 | pages = 1–13 | date = January 2002 | pmid = 11914636 | doi = 10.1097/00001813-200201000-00001 }}</ref>
|-  
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| Inhibition of cyclin D1-CDK4/6
| Inhibition of cyclin D1-CDK4/6
| Small molecule CDK inhibitors <ref>{{cite journal | vauthors = Lapenna S, Giordano A | title = Cell cycle kinases as therapeutic targets for cancer | journal = Nature Reviews. Drug Discovery | volume = 8 | issue = 7 | pages = 547–66 | date = Jul 2009 | pmid = 19568282 | doi = 10.1038/nrd2907 }}</ref><ref>{{cite journal | vauthors = Shapiro GI | title = Cyclin-dependent kinase pathways as targets for cancer treatment | journal = Journal of Clinical Oncology | volume = 24 | issue = 11 | pages = 1770–83 | date = Apr 2006 | pmid = 16603719 | doi = 10.1200/JCO.2005.03.7689 }}</ref>
| Small molecule CDK inhibitors <ref>{{cite journal | vauthors = Lapenna S, Giordano A | title = Cell cycle kinases as therapeutic targets for cancer | journal = Nature Reviews. Drug Discovery | volume = 8 | issue = 7 | pages = 547–66 | date = July 2009 | pmid = 19568282 | doi = 10.1038/nrd2907 }}</ref><ref>{{cite journal | vauthors = Shapiro GI | title = Cyclin-dependent kinase pathways as targets for cancer treatment | journal = Journal of Clinical Oncology | volume = 24 | issue = 11 | pages = 1770–83 | date = April 2006 | pmid = 16603719 | doi = 10.1200/JCO.2005.03.7689 }}</ref>
|}
|}


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Cyclin D1 has been shown to [[Protein-protein interaction|interact]] with:
Cyclin D1 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[Androgen receptor|NR3C4]],<ref name = pmid11328859 >{{cite journal | vauthors = Reutens AT, Fu M, Wang C, Albanese C, McPhaul MJ, Sun Z, Balk SP, Jänne OA, Palvimo JJ, Pestell RG | title = Cyclin D1 binds the androgen receptor and regulates hormone-dependent signaling in a p300/CBP-associated factor (P/CAF)-dependent manner | journal = Mol. Endocrinol. | volume = 15 | issue = 5 | pages = 797–811  | date = May 2001 | pmid = 11328859 | doi = 10.1210/mend.15.5.0641 }}</ref><ref name = pmid15558026>{{cite journal | vauthors = Petre-Draviam CE, Williams EB, Burd CJ, Gladden A, Moghadam H, Meller J, Diehl JA, Knudsen KE | title = A central domain of cyclin D1 mediates nuclear receptor corepressor activity | journal = Oncogene | volume = 24 | issue = 3 | pages = 431–44 | date = January 2005 | pmid = 15558026 | doi = 10.1038/sj.onc.1208200 }}</ref><ref name = pmid10344732>{{cite journal | vauthors = Knudsen KE, Cavenee WK, Arden KC | title = D-type cyclins complex with the androgen receptor and inhibit its transcriptional transactivation ability | journal = Cancer Res. | volume = 59 | issue = 10 | pages = 2297–301 | date = May 1999 | pmid = 10344732 | doi =  }}</ref>
* [[Androgen receptor|NR3C4]],<ref name="Reutens AT p300"/><ref name = pmid15558026>{{cite journal | vauthors = Petre-Draviam CE, Williams EB, Burd CJ, Gladden A, Moghadam H, Meller J, Diehl JA, Knudsen KE | title = A central domain of cyclin D1 mediates nuclear receptor corepressor activity | journal = Oncogene | volume = 24 | issue = 3 | pages = 431–44 | date = January 2005 | pmid = 15558026 | doi = 10.1038/sj.onc.1208200 }}</ref><ref name = pmid10344732>{{cite journal | vauthors = Knudsen KE, Cavenee WK, Arden KC | title = D-type cyclins complex with the androgen receptor and inhibit its transcriptional transactivation ability | journal = Cancer Research | volume = 59 | issue = 10 | pages = 2297–301 | date = May 1999 | pmid = 10344732 | doi =  }}</ref>
* [[BRCA1]],<ref name = pmid16061635 >{{cite journal | vauthors = Wang C, Fan S, Li Z, Fu M, Rao M, Ma Y, Lisanti MP, Albanese C, Katzenellenbogen BS, Kushner PJ, Weber B, Rosen EM, Pestell RG | title = Cyclin D1 antagonizes BRCA1 repression of estrogen receptor alpha activity | journal = Cancer Res. | volume = 65 | issue = 15 | pages = 6557–67 | date = Aug 2005 | pmid = 16061635 | doi = 10.1158/0008-5472.CAN-05-0486 }}</ref><ref name = pmid23864650 >{{cite journal | vauthors = Casimiro MC, Wang C, Li Z, Di Sante G, Willmart NE, Addya S, Chen L, Liu Y, Lisanti MP, Pestell RG | title = Cyclin D1 determines estrogen signaling in the mammary gland in vivo | journal = Mol. Endocrinol. | volume = 27 | issue = 9 | pages = 1415–28 | date = Sep 2013 | pmid = 23864650 | pmc = 3753428 | doi = 10.1210/me.2013-1065 }}</ref>
* [[BRCA1]],<ref name = pmid16061635 >{{cite journal | vauthors = Wang C, Fan S, Li Z, Fu M, Rao M, Ma Y, Lisanti MP, Albanese C, Katzenellenbogen BS, Kushner PJ, Weber B, Rosen EM, Pestell RG | title = Cyclin D1 antagonizes BRCA1 repression of estrogen receptor alpha activity | journal = Cancer Research | volume = 65 | issue = 15 | pages = 6557–67 | date = August 2005 | pmid = 16061635 | doi = 10.1158/0008-5472.CAN-05-0486 }}</ref><ref name = pmid23864650 >{{cite journal | vauthors = Casimiro MC, Wang C, Li Z, Di Sante G, Willmart NE, Addya S, Chen L, Liu Y, Lisanti MP, Pestell RG | title = Cyclin D1 determines estrogen signaling in the mammary gland in vivo | journal = Molecular Endocrinology | volume = 27 | issue = 9 | pages = 1415–28 | date = September 2013 | pmid = 23864650 | pmc = 3753428 | doi = 10.1210/me.2013-1065 }}</ref>
* [[CCNDBP1]],<ref name = pmid10801854>{{cite journal | vauthors = Xia C, Bao Z, Tabassam F, Ma W, Qiu M, Hua S, Liu M | title = GCIP, a novel human grap2 and cyclin D interacting protein, regulates E2F-mediated transcriptional activity | journal = J. Biol. Chem. | volume = 275 | issue = 27 | pages = 20942–8 | date = July 2000 | pmid = 10801854 | doi = 10.1074/jbc.M002598200 }}</ref>  
* [[CCNDBP1]],<ref name = pmid10801854>{{cite journal | vauthors = Xia C, Bao Z, Tabassam F, Ma W, Qiu M, Hua S, Liu M | title = GCIP, a novel human grap2 and cyclin D interacting protein, regulates E2F-mediated transcriptional activity | journal = The Journal of Biological Chemistry | volume = 275 | issue = 27 | pages = 20942–8 | date = July 2000 | pmid = 10801854 | doi = 10.1074/jbc.M002598200 }}</ref>  
* [[Cyclin-dependent kinase 4|CDK4]],<ref name = pmid10580009>{{cite journal | vauthors = Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E | title = Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1) | journal = Genes Dev. | volume = 13 | issue = 22 | pages = 3027–33 | date = November 1999 | pmid = 10580009 | pmc = 317153 | doi = 10.1101/gad.13.22.3027 }}</ref><ref name = pmid8259215>{{cite journal | vauthors = Serrano M, Hannon GJ, Beach D | title = A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 | journal = Nature | volume = 366 | issue = 6456 | pages = 704–7 | date = December 1993 | pmid = 8259215 | doi = 10.1038/366704a0 | bibcode = 1993Natur.366..704S }}</ref><ref name = pmid11360184>{{cite journal | vauthors = Lin J, Jinno S, Okayama H | title = Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence | journal = Oncogene | volume = 20 | issue = 16 | pages = 2000–9 | date = April 2001 | pmid = 11360184 | doi = 10.1038/sj.onc.1204375 }}</ref><ref name = pmid9837900>{{cite journal | vauthors = Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N | title = Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1 | journal = J. Biol. Chem. | volume = 273 | issue = 50 | pages = 33279–86 | date = December 1998 | pmid = 9837900 | doi = 10.1074/jbc.273.50.33279 }}</ref><ref name = pmid10908655>{{cite journal | vauthors = Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM | title = Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 16 | pages = 9042–6 | date = August 2000 | pmid = 10908655 | pmc = 16818 | doi = 10.1073/pnas.160016897 | bibcode = 2000PNAS...97.9042C }}</ref><ref name = pmid9228064>{{cite journal | vauthors = Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, Price S, Webster KR | title = Identification of CDK4 sequences involved in cyclin D1 and p16 binding | journal = J. Biol. Chem. | volume = 272 | issue = 30 | pages = 18869–74 | date = July 1997 | pmid = 9228064 | doi = 10.1074/jbc.272.30.18869 }}</ref>  
* [[Cyclin-dependent kinase 4|CDK4]],<ref name = pmid10580009>{{cite journal | vauthors = Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E | title = Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1) | journal = Genes & Development | volume = 13 | issue = 22 | pages = 3027–33 | date = November 1999 | pmid = 10580009 | pmc = 317153 | doi = 10.1101/gad.13.22.3027 }}</ref><ref name = pmid8259215>{{cite journal | vauthors = Serrano M, Hannon GJ, Beach D | title = A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 | journal = Nature | volume = 366 | issue = 6456 | pages = 704–7 | date = December 1993 | pmid = 8259215 | doi = 10.1038/366704a0 | bibcode = 1993Natur.366..704S }}</ref><ref name = pmid11360184>{{cite journal | vauthors = Lin J, Jinno S, Okayama H | title = Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence | journal = Oncogene | volume = 20 | issue = 16 | pages = 2000–9 | date = April 2001 | pmid = 11360184 | doi = 10.1038/sj.onc.1204375 }}</ref><ref name = pmid9837900>{{cite journal | vauthors = Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N | title = Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 50 | pages = 33279–86 | date = December 1998 | pmid = 9837900 | doi = 10.1074/jbc.273.50.33279 }}</ref><ref name = pmid10908655>{{cite journal | vauthors = Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM | title = Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 16 | pages = 9042–6 | date = August 2000 | pmid = 10908655 | pmc = 16818 | doi = 10.1073/pnas.160016897 | bibcode = 2000PNAS...97.9042C }}</ref><ref name = pmid9228064>{{cite journal | vauthors = Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, Price S, Webster KR | title = Identification of CDK4 sequences involved in cyclin D1 and p16 binding | journal = The Journal of Biological Chemistry | volume = 272 | issue = 30 | pages = 18869–74 | date = July 1997 | pmid = 9228064 | doi = 10.1074/jbc.272.30.18869 }}</ref>  
* [[Cyclin-dependent kinase 6|CDK6]],<ref name = pmid10580009/><ref name = pmid11360184/>
* [[Cyclin-dependent kinase 6|CDK6]],<ref name = pmid10580009/><ref name = pmid11360184/>
* [[Estrogen receptor alpha|ESR1]]<ref name="pmid16061635"/><ref name="pmid23864650"/><ref name = pmid9271411 >{{cite journal | vauthors = Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M, Ewen ME | title = Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4 | journal = Mol. Cell. Biol. | volume = 17 | issue = 9 | pages = 5338–47 | date = Sep 1997 | pmid = 9271411 | pmc = 232384 | doi =  }}</ref><ref name = pmid9039267>{{cite journal | vauthors = Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ | title = CDK-independent activation of estrogen receptor by cyclin D1 | journal = Cell | volume = 88 | issue = 3 | pages = 405–15  | date = February 1997 | pmid = 9039267 | doi = 10.1016/s0092-8674(00)81879-6 }}</ref>
* [[Estrogen receptor alpha|ESR1]]<ref name="pmid16061635"/><ref name="pmid23864650"/><ref name = pmid9271411 >{{cite journal | vauthors = Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M, Ewen ME | title = Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4 | journal = Molecular and Cellular Biology | volume = 17 | issue = 9 | pages = 5338–47 | date = September 1997 | pmid = 9271411 | pmc = 232384 | doi =  }}</ref><ref name = pmid9039267 />
* [[HDAC3]],<ref name = pmid15558026/><ref name = pmid12048199/>
* [[HDAC3]],<ref name = pmid15558026/><ref name = pmid12048199/>
* [[HDACs]]<ref name = "Fu_2005"/>
* [[HDACs]]<ref name = "Fu_2005"/>
* [[NEUROD1]],<ref name = pmid11788592>{{cite journal | vauthors = Ratineau C, Petry MW, Mutoh H, Leiter AB | title = Cyclin D1 represses the basic helix-loop-helix transcription factor, BETA2/NeuroD | journal = J. Biol. Chem. | volume = 277 | issue = 11 | pages = 8847–53 | date = March 2002 | pmid = 11788592 | doi = 10.1074/jbc.M110747200 }}</ref>  
* [[NEUROD1]],<ref name = pmid11788592>{{cite journal | vauthors = Ratineau C, Petry MW, Mutoh H, Leiter AB | title = Cyclin D1 represses the basic helix-loop-helix transcription factor, BETA2/NeuroD | journal = The Journal of Biological Chemistry | volume = 277 | issue = 11 | pages = 8847–53 | date = March 2002 | pmid = 11788592 | doi = 10.1074/jbc.M110747200 }}</ref>  
* [[Nuclear receptor coactivator 1|NCOA1]],<ref name = pmid9832502>{{cite journal | vauthors = Zwijsen RM, Buckle RS, Hijmans EM, Loomans CJ, Bernards R | title = Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1 | journal = Genes Dev. | volume = 12 | issue = 22 | pages = 3488–98 | date = November 1998 | pmid = 9832502 | pmc = 317237 | doi = 10.1101/gad.12.22.3488 }}</ref>
* [[Nuclear receptor coactivator 1|NCOA1]],<ref name = pmid9832502>{{cite journal | vauthors = Zwijsen RM, Buckle RS, Hijmans EM, Loomans CJ, Bernards R | title = Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1 | journal = Genes & Development | volume = 12 | issue = 22 | pages = 3488–98 | date = November 1998 | pmid = 9832502 | pmc = 317237 | doi = 10.1101/gad.12.22.3488 }}</ref>
* [[NRF1]],<ref name = pmid16864783>{{cite journal | vauthors = Wang C, Li Z, Lu Y, Du R, Katiyar S, Yang J, Fu M, Leader JE, Quong A, Novikoff PM, Pestell RG | title = Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 31 | pages = 11567–72 | date = July 2006 | pmid = 16864783 | pmc = 1518800 | doi = 10.1073/pnas.0603363103 | bibcode = 2006PNAS..10311567W }}</ref>
* [[NRF1]],<ref name = pmid16864783>{{cite journal | vauthors = Wang C, Li Z, Lu Y, Du R, Katiyar S, Yang J, Fu M, Leader JE, Quong A, Novikoff PM, Pestell RG | title = Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 31 | pages = 11567–72 | date = August 2006 | pmid = 16864783 | pmc = 1518800 | doi = 10.1073/pnas.0603363103 | bibcode = 2006PNAS..10311567W }}</ref>
* [[p300-CBP coactivator family|p300]],<ref name = pmid15951563 >{{cite journal | vauthors = Fu M, Wang C, Rao M, Wu X, Bouras T, Zhang X, Li Z, Jiao X, Yang J, Li A, Perkins ND, Thimmapaya B, Kung AL, Munoz A, Giordano A, Lisanti MP, Pestell RG | title = Cyclin D1 represses p300 transactivation through a cyclin-dependent kinase-independent mechanism | journal = J. Biol. Chem. | volume = 280 | issue = 33 | pages = 29728–42 | date = Aug 2005 | pmid = 15951563 | doi = 10.1074/jbc.M503188200 }}</ref>
* [[p300-CBP coactivator family|p300]],<ref name = pmid15951563 >{{cite journal | vauthors = Fu M, Wang C, Rao M, Wu X, Bouras T, Zhang X, Li Z, Jiao X, Yang J, Li A, Perkins ND, Thimmapaya B, Kung AL, Munoz A, Giordano A, Lisanti MP, Pestell RG | title = Cyclin D1 represses p300 transactivation through a cyclin-dependent kinase-independent mechanism | journal = The Journal of Biological Chemistry | volume = 280 | issue = 33 | pages = 29728–42 | date = August 2005 | pmid = 15951563 | doi = 10.1074/jbc.M503188200 }}</ref>
* [[PACSIN2]],<ref name = pmid21200149 >{{cite journal | vauthors = Meng H, Tian L, Zhou J, Li Z, Jiao X, Li WW, Plomann M, Xu Z, Lisanti MP, Wang C, Pestell RG | title = PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate splice form cyclin D1b | journal = Cell Cycle | volume = 10 | issue = 1 | pages = 73–81 | date = Jan 2011 | pmid = 21200149 | pmc = 3048077 | doi = 10.4161/cc.10.1.14243 }}</ref>
* [[PACSIN2]],<ref name = pmid21200149 >{{cite journal | vauthors = Meng H, Tian L, Zhou J, Li Z, Jiao X, Li WW, Plomann M, Xu Z, Lisanti MP, Wang C, Pestell RG | title = PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate splice form cyclin D1b | journal = Cell Cycle | volume = 10 | issue = 1 | pages = 73–81 | date = January 2011 | pmid = 21200149 | pmc = 3048077 | doi = 10.4161/cc.10.1.14243 }}</ref>
* [[PCNA]],<ref name = pmid7908906>{{cite journal | vauthors = Matsuoka S, Yamaguchi M, Matsukage A | title = D-type cyclin-binding regions of proliferating cell nuclear antigen | journal = J. Biol. Chem. | volume = 269 | issue = 15 | pages = 11030–6 | date = April 1994 | pmid = 7908906 | doi =  }}</ref><ref name = pmid8101826>{{cite journal | vauthors = Xiong Y, Zhang H, Beach D | title = Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation | journal = Genes Dev. | volume = 7 | issue = 8 | pages = 1572–83 | date = August 1993 | pmid = 8101826 | doi = 10.1101/gad.7.8.1572 }}</ref>
* [[PCNA]],<ref name = pmid7908906>{{cite journal | vauthors = Matsuoka S, Yamaguchi M, Matsukage A | title = D-type cyclin-binding regions of proliferating cell nuclear antigen | journal = The Journal of Biological Chemistry | volume = 269 | issue = 15 | pages = 11030–6 | date = April 1994 | pmid = 7908906 | doi =  }}</ref><ref name = pmid8101826>{{cite journal | vauthors = Xiong Y, Zhang H, Beach D | title = Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation | journal = Genes & Development | volume = 7 | issue = 8 | pages = 1572–83 | date = August 1993 | pmid = 8101826 | doi = 10.1101/gad.7.8.1572 }}</ref>
* [[PPARG]],<ref name = pmid12917338 >{{cite journal | vauthors = Wang C, Pattabiraman N, Zhou JN, Fu M, Sakamaki T, Albanese C, Li Z, Wu K, Hulit J, Neumeister P, Novikoff PM, Brownlee M, Scherer PE, Jones JG, Whitney KD, Donehower LA, Harris EL, Rohan T, Johns DC, Pestell RG | title = Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation | journal = Mol. Cell. Biol. | volume = 23 | issue = 17 | pages = 6159–73 | date = Sep 2003 | pmid = 12917338 | pmc = 180960 | doi = 10.1128/mcb.23.17.6159-6173.2003 }}</ref>
* [[PPARG]],<ref name = pmid12917338 >{{cite journal | vauthors = Wang C, Pattabiraman N, Zhou JN, Fu M, Sakamaki T, Albanese C, Li Z, Wu K, Hulit J, Neumeister P, Novikoff PM, Brownlee M, Scherer PE, Jones JG, Whitney KD, Donehower LA, Harris EL, Rohan T, Johns DC, Pestell RG | title = Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation | journal = Molecular and Cellular Biology | volume = 23 | issue = 17 | pages = 6159–73 | date = September 2003 | pmid = 12917338 | pmc = 180960 | doi = 10.1128/mcb.23.17.6159-6173.2003 }}</ref>
* [[RAD51]],<ref name = pmid20940395>{{cite journal | vauthors = Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG | title = Alternative cyclin D1 splice forms differentially regulate the DNA damage response | journal = Cancer Res. | volume = 70 | issue = 21 | pages = 8802–11 | date = November 2010 | pmid = 20940395 | pmc = 2970762 | doi = 10.1158/0008-5472.CAN-10-0312 }}</ref>
* [[RAD51]],<ref name = pmid20940395>{{cite journal | vauthors = Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG | title = Alternative cyclin D1 splice forms differentially regulate the DNA damage response | journal = Cancer Research | volume = 70 | issue = 21 | pages = 8802–11 | date = November 2010 | pmid = 20940395 | pmc = 2970762 | doi = 10.1158/0008-5472.CAN-10-0312 }}</ref>
* [[Retinoblastoma protein|RB1]],<ref name = pmid11126356>{{cite journal | vauthors = Siegert JL, Rushton JJ, Sellers WR, Kaelin WG, Robbins PD | title = Cyclin D1 suppresses retinoblastoma protein-mediated inhibition of TAFII250 kinase activity | journal = Oncogene | volume = 19 | issue = 50 | pages = 5703–11 | date = November 2000 | pmid = 11126356 | doi = 10.1038/sj.onc.1203966 }}</ref><ref name = pmid8490963>{{cite journal | vauthors = Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA | title = Physical interaction of the retinoblastoma protein with human D cyclins | journal = Cell | volume = 73 | issue = 3 | pages = 499–511 | date = May 1993 | pmid = 8490963 | doi = 10.1016/0092-8674(93)90137-f }}</ref>  
* [[Retinoblastoma protein|RB1]],<ref name = pmid11126356>{{cite journal | vauthors = Siegert JL, Rushton JJ, Sellers WR, Kaelin WG, Robbins PD | title = Cyclin D1 suppresses retinoblastoma protein-mediated inhibition of TAFII250 kinase activity | journal = Oncogene | volume = 19 | issue = 50 | pages = 5703–11 | date = November 2000 | pmid = 11126356 | doi = 10.1038/sj.onc.1203966 }}</ref><ref name = pmid8490963>{{cite journal | vauthors = Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA | title = Physical interaction of the retinoblastoma protein with human D cyclins | journal = Cell | volume = 73 | issue = 3 | pages = 499–511 | date = May 1993 | pmid = 8490963 | doi = 10.1016/0092-8674(93)90137-f }}</ref>  
* [[TAF1]],<ref name = pmid11126356/><ref name = pmid9926939>{{cite journal | vauthors = Adnane J, Shao Z, Robbins PD | title = Cyclin D1 associates with the TBP-associated factor TAF(II)250 to regulate Sp1-mediated transcription | journal = Oncogene | volume = 18 | issue = 1 | pages = 239–47 | date = January 1999 | pmid = 9926939 | doi = 10.1038/sj.onc.1202297 }}</ref>  and
* [[TAF1]],<ref name = pmid11126356/><ref name = pmid9926939>{{cite journal | vauthors = Adnane J, Shao Z, Robbins PD | title = Cyclin D1 associates with the TBP-associated factor TAF(II)250 to regulate Sp1-mediated transcription | journal = Oncogene | volume = 18 | issue = 1 | pages = 239–47 | date = January 1999 | pmid = 9926939 | doi = 10.1038/sj.onc.1202297 }}</ref>  and
* [[Thyroid hormone receptor beta|NR1A2]].<ref name = pmid12048199>{{cite journal | vauthors = Lin HM, Zhao L, Cheng SY | title = Cyclin D1 Is a Ligand-independent Co-repressor for Thyroid Hormone Receptors | journal = J. Biol. Chem. | volume = 277 | issue = 32 | pages = 28733–41 | date = August 2002 | pmid = 12048199 | doi = 10.1074/jbc.M203380200 }}</ref>  
* [[Thyroid hormone receptor beta|NR1A2]].<ref name = pmid12048199>{{cite journal | vauthors = Lin HM, Zhao L, Cheng SY | title = Cyclin D1 Is a Ligand-independent Co-repressor for Thyroid Hormone Receptors | journal = The Journal of Biological Chemistry | volume = 277 | issue = 32 | pages = 28733–41 | date = August 2002 | pmid = 12048199 | doi = 10.1074/jbc.M203380200 }}</ref>  
{{Div col end}}
{{Div col end}}


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== References ==
== References ==
{{reflist|2}}
{{reflist|32em}}


== Further reading ==
== Further reading ==
{{refbegin|2}}
{{refbegin|32em}}
* {{cite journal | vauthors = Akita H | title = [Prognostic importance of altered expression of cell cycle regulators in lung cancer] | journal = Nippon Rinsho | volume = 60 Suppl 5 | issue =  | pages = 267–71 | year = 2002 | pmid = 12101670 | doi =  }}
* {{cite journal | vauthors = Akita H | title = [Prognostic importance of altered expression of cell cycle regulators in lung cancer] | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 60 Suppl 5 | issue =  | pages = 267–71 | date = May 2002 | pmid = 12101670 | doi =  }}
* {{cite journal | vauthors = Chung DC | title = Cyclin D1 in human neuroendocrine: tumorigenesis | journal = Ann. N. Y. Acad. Sci. | volume = 1014 | issue =  | pages = 209–17 | year = 2004 | pmid = 15153436 | doi = 10.1196/annals.1294.022 | bibcode = 2004NYASA1014..209C }}
* {{cite journal | vauthors = Chung DC | title = Cyclin D1 in human neuroendocrine: tumorigenesis | journal = Annals of the New York Academy of Sciences | volume = 1014 | issue =  1| pages = 209–17 | date = April 2004 | pmid = 15153436 | doi = 10.1196/annals.1294.022 | bibcode = 2004NYASA1014..209C }}
* {{cite journal | vauthors = Jain S, Khuri FR, Shin DM | title = Prevention of head and neck cancer: current status and future prospects | journal = Curr Probl Cancer | volume = 28 | issue = 5 | pages = 265–86 | year = 2004 | pmid = 15375804 | doi = 10.1016/j.currproblcancer.2004.05.003 }}
* {{cite journal | vauthors = Jain S, Khuri FR, Shin DM | title = Prevention of head and neck cancer: current status and future prospects | journal = Current Problems in Cancer | volume = 28 | issue = 5 | pages = 265–86 | year = 2004 | pmid = 15375804 | doi = 10.1016/j.currproblcancer.2004.05.003 }}
* {{cite journal | vauthors = Gladden AB, Diehl JA | title = Location, location, location: the role of cyclin D1 nuclear localization in cancer | journal = J. Cell. Biochem. | volume = 96 | issue = 5 | pages = 906–13 | year = 2005 | pmid = 16163738 | doi = 10.1002/jcb.20613 }}
* {{cite journal | vauthors = Gladden AB, Diehl JA | title = Location, location, location: the role of cyclin D1 nuclear localization in cancer | journal = Journal of Cellular Biochemistry | volume = 96 | issue = 5 | pages = 906–13 | date = December 2005 | pmid = 16163738 | doi = 10.1002/jcb.20613 }}
* {{cite journal | vauthors = Walker JL, Assoian RK | title = Integrin-dependent signal transduction regulating cyclin D1 expression and G1 phase cell cycle progression | journal = Cancer Metastasis Rev. | volume = 24 | issue = 3 | pages = 383–93 | year = 2005 | pmid = 16258726 | doi = 10.1007/s10555-005-5130-7 }}
* {{cite journal | vauthors = Walker JL, Assoian RK | title = Integrin-dependent signal transduction regulating cyclin D1 expression and G1 phase cell cycle progression | journal = Cancer Metastasis Reviews | volume = 24 | issue = 3 | pages = 383–93 | date = September 2005 | pmid = 16258726 | doi = 10.1007/s10555-005-5130-7 }}
* {{cite journal | vauthors = Gautschi O, Ratschiller D, Gugger M, Betticher DC, Heighway J | title = Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation | journal = Lung Cancer | volume = 55 | issue = 1 | pages = 1–14 | year = 2007 | pmid = 17070615 | doi = 10.1016/j.lungcan.2006.09.024 }}
* {{cite journal | vauthors = Gautschi O, Ratschiller D, Gugger M, Betticher DC, Heighway J | title = Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation | journal = Lung Cancer | volume = 55 | issue = 1 | pages = 1–14 | date = January 2007 | pmid = 17070615 | doi = 10.1016/j.lungcan.2006.09.024 }}
* {{cite journal | vauthors = Li Z, Wang C, Prendergast GC, Pestell RG | title = Cyclin D1 functions in cell migration | journal = Cell Cycle | volume = 5 | issue = 21 | pages = 2440–2 | year = 2006 | pmid = 17106256 | doi = 10.4161/cc.5.21.3428 }}
* {{cite journal | vauthors = Li Z, Wang C, Prendergast GC, Pestell RG | title = Cyclin D1 functions in cell migration | journal = Cell Cycle | volume = 5 | issue = 21 | pages = 2440–2 | date = November 2006 | pmid = 17106256 | doi = 10.4161/cc.5.21.3428 }}
* {{cite journal | vauthors = Zhang T, Liu WD, Saunee NA, Breslin MB, Lan MS | title = Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4 binding and induces cell cycle arrest | journal = J. Biol. Chem. | volume = 284 | issue = 9 | pages = 5574–81 | year = 2009 | pmid = 19124461 | pmc = 2645817 | doi = 10.1074/jbc.M808843200 }}
* {{cite journal | vauthors = Zhang T, Liu WD, Saunee NA, Breslin MB, Lan MS | title = Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4 binding and induces cell cycle arrest | journal = The Journal of Biological Chemistry | volume = 284 | issue = 9 | pages = 5574–81 | date = February 2009 | pmid = 19124461 | pmc = 2645817 | doi = 10.1074/jbc.M808843200 }}
* {{cite journal | vauthors = Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ, Look AT | title = Genomic organization, chromosomal localization, and independent expression of human cyclin D genes | journal = Genomics | volume = 13 | issue = 3 | pages = 565–74 | year = 1992 | pmid = 1386335 | doi = 10.1016/0888-7543(92)90126-D }}
* {{cite journal | vauthors = Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ, Look AT | title = Genomic organization, chromosomal localization, and independent expression of human cyclin D genes | journal = Genomics | volume = 13 | issue = 3 | pages = 565–74 | date = July 1992 | pmid = 1386335 | doi = 10.1016/0888-7543(92)90126-D }}
* {{cite journal | vauthors = Schuuring E, Verhoeven E, Mooi WJ, Michalides RJ | title = Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas | journal = Oncogene | volume = 7 | issue = 2 | pages = 355–61 | year = 1992 | pmid = 1532244 | doi =  }}
* {{cite journal | vauthors = Schuuring E, Verhoeven E, Mooi WJ, Michalides RJ | title = Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas | journal = Oncogene | volume = 7 | issue = 2 | pages = 355–61 | date = February 1992 | pmid = 1532244 | doi =  }}
* {{cite journal | vauthors = Seto M, Yamamoto K, Iida S, Akao Y, Utsumi KR, Kubonishi I, Miyoshi I, Ohtsuki T, Yawata Y, Namba M | title = Gene rearrangement and overexpression of PRAD1 in lymphoid malignancy with t(11;14)(q13;q32) translocation | journal = Oncogene | volume = 7 | issue = 7 | pages = 1401–6 | year = 1992 | pmid = 1535701 | doi =  }}
* {{cite journal | vauthors = Seto M, Yamamoto K, Iida S, Akao Y, Utsumi KR, Kubonishi I, Miyoshi I, Ohtsuki T, Yawata Y, Namba M | title = Gene rearrangement and overexpression of PRAD1 in lymphoid malignancy with t(11;14)(q13;q32) translocation | journal = Oncogene | volume = 7 | issue = 7 | pages = 1401–6 | date = July 1992 | pmid = 1535701 | doi =  }}
* {{cite journal | vauthors = Rosenberg CL, Wong E, Petty EM, Bale AE, Tsujimoto Y, Harris NL, Arnold A | title = PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 88 | issue = 21 | pages = 9638–42 | year = 1991 | pmid = 1682919 | pmc = 52773 | doi = 10.1073/pnas.88.21.9638 | bibcode = 1991PNAS...88.9638R }}
* {{cite journal | vauthors = Rosenberg CL, Wong E, Petty EM, Bale AE, Tsujimoto Y, Harris NL, Arnold A | title = PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 21 | pages = 9638–42 | date = November 1991 | pmid = 1682919 | pmc = 52773 | doi = 10.1073/pnas.88.21.9638 | bibcode = 1991PNAS...88.9638R }}
* {{cite journal | vauthors = Xiong Y, Connolly T, Futcher B, Beach D | title = Human D-type cyclin | journal = Cell | volume = 65 | issue = 4 | pages = 691–9 | year = 1991 | pmid = 1827756 | doi = 10.1016/0092-8674(91)90100-D }}
* {{cite journal | vauthors = Xiong Y, Connolly T, Futcher B, Beach D | title = Human D-type cyclin | journal = Cell | volume = 65 | issue = 4 | pages = 691–9 | date = May 1991 | pmid = 1827756 | doi = 10.1016/0092-8674(91)90100-D }}
* {{cite journal | vauthors = Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC | title = Characterization of a candidate bcl-1 gene | journal = Mol. Cell. Biol. | volume = 11 | issue = 10 | pages = 4846–53 | year = 1991 | pmid = 1833629 | pmc = 361453 | doi =  }}
* {{cite journal | vauthors = Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC | title = Characterization of a candidate bcl-1 gene | journal = Molecular and Cellular Biology | volume = 11 | issue = 10 | pages = 4846–53 | date = October 1991 | pmid = 1833629 | pmc = 361453 | doi =  }}
* {{cite journal | vauthors = Tsujimoto Y, Yunis J, Onorato-Showe L, Erikson J, Nowell PC, Croce CM | title = Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation | journal = Science | volume = 224 | issue = 4656 | pages = 1403–6 | year = 1984 | pmid = 6610211 | doi = 10.1126/science.6610211 | bibcode = 1984Sci...224.1403T }}
* {{cite journal | vauthors = Tsujimoto Y, Yunis J, Onorato-Showe L, Erikson J, Nowell PC, Croce CM | title = Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation | journal = Science | volume = 224 | issue = 4656 | pages = 1403–6 | date = June 1984 | pmid = 6610211 | doi = 10.1126/science.6610211 | bibcode = 1984Sci...224.1403T }}
* {{cite journal | vauthors = Hall M, Bates S, Peters G | title = Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins | journal = Oncogene | volume = 11 | issue = 8 | pages = 1581–8 | year = 1995 | pmid = 7478582 | doi =  }}
* {{cite journal | vauthors = Hall M, Bates S, Peters G | title = Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins | journal = Oncogene | volume = 11 | issue = 8 | pages = 1581–8 | date = October 1995 | pmid = 7478582 | doi =  }}
* {{cite journal | vauthors = Tassan JP, Jaquenoud M, Léopold P, Schultz SJ, Nigg EA | title = Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 19 | pages = 8871–5 | year = 1995 | pmid = 7568034 | pmc = 41069 | doi = 10.1073/pnas.92.19.8871 | bibcode = 1995PNAS...92.8871T }}
* {{cite journal | vauthors = Tassan JP, Jaquenoud M, Léopold P, Schultz SJ, Nigg EA | title = Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 19 | pages = 8871–5 | date = September 1995 | pmid = 7568034 | pmc = 41069 | doi = 10.1073/pnas.92.19.8871 | bibcode = 1995PNAS...92.8871T }}
* {{cite journal | vauthors = Fornaro M, Dell'Arciprete R, Stella M, Bucci C, Nutini M, Capri MG, Alberti S | title = Cloning of the gene encoding Trop-2, a cell-surface glycoprotein expressed by human carcinomas | journal = Int. J. Cancer | volume = 62 | issue = 5 | pages = 610–8 | year = 1995 | pmid = 7665234 | doi = 10.1002/ijc.2910620520 }}
* {{cite journal | vauthors = Fornaro M, Dell'Arciprete R, Stella M, Bucci C, Nutini M, Capri MG, Alberti S | title = Cloning of the gene encoding Trop-2, a cell-surface glycoprotein expressed by human carcinomas | journal = International Journal of Cancer | volume = 62 | issue = 5 | pages = 610–8 | date = September 1995 | pmid = 7665234 | doi = 10.1002/ijc.2910620520 }}
* {{cite journal | vauthors = Motokura T, Arnold A | title = PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint | journal = Genes Chromosomes Cancer | volume = 7 | issue = 2 | pages = 89–95 | year = 1993 | pmid = 7687458 | doi = 10.1002/gcc.2870070205 }}
* {{cite journal | vauthors = Motokura T, Arnold A | title = PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint | journal = Genes, Chromosomes & Cancer | volume = 7 | issue = 2 | pages = 89–95 | date = June 1993 | pmid = 7687458 | doi = 10.1002/gcc.2870070205 }}
{{refend}}
{{refend}}


{{Cell cycle proteins}}
{{Cell cycle proteins}}

Latest revision as of 14:50, 4 October 2018

See also: Cyclin D
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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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View/Edit Human

Cyclin D1 is a protein that in humans is encoded by the CCND1 gene.[1][2]

Gene expression

The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs long, and translates into 295 amino acids.[3] Cyclin D1 is expressed in all adult human tissues with the exception of cells derived from bone marrow stem cell lines (both lymphoid and myeloid).[4][5]

Protein structure

Cyclin D1 is composed of the following protein domains and motifs:[6][7]

  • retinoblastoma protein (pRb) binding motif;
  • cyclin box domain for cyclin-dependent kinase (CDK) binding and CDK inhibitor binding;
  • LxxLL binding motif for co-activator recruitment;
  • PEST sequence that may mark the protein for degradation;
  • threonine residue (threonine 286) that controls nuclear export and protein stability.

Function

The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Cyclins function as regulators of CDKs (Cyclin-dependent kinase). Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis.[8]

File:Mantle cell lymphoma - intermed mag - cyclin D1.jpg
Micrograph of cyclin D1 staining in a mantle cell lymphoma.

Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.

Cyclin D1 has been found to be overexpressed in breast carcinoma. Its potential use as a biomarker was suggested.[9]

Normal function

Cyclin D1 was originally cloned as a breakpoint rearrangement in parathyroid adenoma[10] and was shown to be required for progression through the G1 phase of the cell cycle to induce cell migration,[11] angiogenesis[12] and to induce the Warburg effect.[13] Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle.[14] During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase.[14] Cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6. The protein dimerizes with CDK4/6 to regulate the G1/S phase transition and entry into the S-phase.

CDK dependent functions

The cyclin D1-CDK4 complex promotes passage through the G1 phase by inhibiting the retinoblastoma protein (pRb).[15] Cyclin D1-CDK4 inhibits pRb through phosphorylation, allowing E2F transcription factors to transcribe genes required for entry into the S phase. Inactive pRb allows cell cycle progression through the G1/S transition and allows for DNA synthesis. Cyclin D1-CDK4 also enables the activation of cyclin E-CDK2 complex by sequestering Cip/Kip family CDK inhibitory proteins p21 and p27, allowing entry into the S phase.[16]

Cyclin D1-CDK4 also associates with several transcription factors and transcriptional co-regulators.[6]

CDK independent functions

Independent of CDK, cyclin D1 binds to nuclear receptors (including estrogen receptor α,[17] thyroid hormone receptor, PPARγ [18][19] and AR[20] ) to regulate cell proliferation, growth, and differentiation. Cyclin D1 also binds to histone acetylases and histone deacetylases to regulate cell proliferation and cell differentiation genes [21][22][20][23] in the early to mid-G1 phase.

Synthesis and degradation

Increasing cyclin D1 levels during the G1 phase is induced by mitogenic growth factors [24] primarily through Ras mediated pathways,[25][26][27] and hormones.[21] These Ras-mediated pathways lead to the increase in transcription of cyclin D1, and inhibit its proteolysis and export from the nucleus.[28] Cyclin D1 is degraded via an ubiquitin-mediated proteolysis pathway at the end of the S-phase. Phosphorylation of cyclin D1’s threonine residue T286 marks the protein for export from the nucleus and proteolytic degradation.[29]

Clinical significance

Deregulation in cancer

Cyclin D1 overexpression has been shown to correlate with early cancer onset and tumor progression [16] and it can lead to oncogenesis by increasing anchorage-independent growth and angiogenesis via VEGF production.[30] Cyclin D1 overexpression can also down-regulate Fas expression, leading to increased chemotherapeutic resistance and protection from apoptosis.[30]

An abundance of cyclin D1 can be caused by various types of deregulation, including:

  • amplification of the CCND1 gene / overexpression of cyclin D1;
  • chromosomal translocation of the CCND1 gene;
  • disruption of nuclear export [31] and proteolysis of cyclin D1[32]
  • induction of transcription by oncogenic Ras, Src, ErbB2 and STATs;[33][34][35][36]

Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis.[37][38] Amplification of the CCND1 gene is present in:

Cyclin D1 overexpression is strongly correlated to ER+ breast cancer[50] and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer.[29][51][52] Overexpression of Cyclin D1b, an isoform, is also present in breast and prostate cancers.[7]

Chromosomal translocation around the cyclin D1 gene locus is often seen in B mantle cell lymphoma. In mantle cell lymphoma, cyclin D1 is translocated to the IgH promoter[53] leading to cyclin D1 overexpression. Chromosomal translocation of the cyclin D1 gene locus is also observed in 15 – 20% of multiple myelomas.[54][55]

Therapeutic target in cancer

Cyclin D1 and the mechanisms it regulates have the potential to be a therapeutic target for cancer drugs:

Target Methods of Inhibition
Inhibition of cyclin D1 Inhibiting translation of cyclin D1 mRNA via mTOR inhibitors [56] and RXR activators.[57][58]
Inducing Cyclin D1 degradation [28] Retinoid mediated cyclin D1 degradation via the ubiquitin proteolytic pathway;[59] Differentiation-inducing factor-1 (DIF-1) induced ubiquitin-dependent degradation;[60] Inhibition of cyclin D1 protein synthesis [61][62]
Inducing nuclear export of Cyclin D1 Histone deacetylase inhibitors (HDACIs) to induce nuclear export of Cyclin D1 [63]
Inhibition of cyclin D1-CDK4/6 Small molecule CDK inhibitors [64][65]

Interactions

Cyclin D1 has been shown to interact with:

See also

References

  1. ↑ Motokura T, Bloom T, Kim HG, Jüppner H, Ruderman JV, Kronenberg HM, Arnold A (April 1991). "A novel cyclin encoded by a bcl1-linked candidate oncogene". Nature. 350 (6318): 512–5. Bibcode:1991Natur.350..512M. doi:10.1038/350512a0. PMID 1826542.
  2. ↑ Lew DJ, Dulić V, Reed SI (September 1991). "Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast". Cell. 66 (6): 1197–206. doi:10.1016/0092-8674(91)90042-W. PMID 1833066.
  3. ↑ ""CCND1" Gene". GeneCards. "Weizmann Institute of Science". 2013. Retrieved May 6, 2015.
  4. ↑ Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC (October 1991). "Characterization of a candidate bcl-1 gene". Molecular and Cellular Biology. 11 (10): 4846–53. PMC 361453. PMID 1833629.
  5. ↑ Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ, Look AT (July 1992). "Genomic organization, chromosomal localization, and independent expression of human cyclin D genes". Genomics. 13 (3): 565–74. doi:10.1016/0888-7543(92)90126-d. PMID 1386335.
  6. ↑ 6.0 6.1 Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (July 2011). "Cyclin D as a therapeutic target in cancer". Nature Reviews. Cancer. 11 (8): 558–72. doi:10.1038/nrc3090. PMID 21734724.
  7. ↑ 7.0 7.1 Knudsen KE, Diehl JA, Haiman CA, Knudsen ES (March 2006). "Cyclin D1: polymorphism, aberrant splicing and cancer risk". Oncogene. 25 (11): 1620–8. doi:10.1038/sj.onc.1209371. PMID 16550162.
  8. ↑ "Entrez Gene: CCND1 cyclin D1".
  9. ↑ He Y, Liu Z, Qiao C, Xu M, Yu J, Li G (January 2014). "Expression and significance of Wnt signaling components and their target genes in breast carcinoma". Molecular Medicine Reports. 9 (1): 137–43. doi:10.3892/mmr.2013.1774. PMID 24190141.
  10. ↑ Motokura T, Bloom T, Kim HG, Jüppner H, Ruderman JV, Kronenberg HM, Arnold A (April 1991). "A novel cyclin encoded by a bcl1-linked candidate oncogene". Nature. 350 (6318): 512–5. Bibcode:1991Natur.350..512M. doi:10.1038/350512a0. PMID 1826542.
  11. ↑ Neumeister P, Pixley FJ, Xiong Y, Xie H, Wu K, Ashton A, Cammer M, Chan A, Symons M, Stanley ER, Pestell RG (May 2003). "Cyclin D1 governs adhesion and motility of macrophages". Molecular Biology of the Cell. 14 (5): 2005–15. doi:10.1091/mbc.02-07-0102. PMC 165093. PMID 12802071.
  12. ↑ Holnthoner W, Pillinger M, Groger M, Wolff K, Ashton AW, Albanese C, Neumeister P, Pestell RG, Petzelbauer P (November 2002). "Fibroblast growth factor-2 induces Lef/Tcf-dependent transcription in human endothelial cells". The Journal of Biological Chemistry. 277 (48): 45847–53. doi:10.1074/jbc.M209354200. PMID 12235165.
  13. ↑ Sakamaki T, Casimiro MC, Ju X, Quong AA, Katiyar S, Liu M, Jiao X, Li A, Zhang X, Lu Y, Wang C, Byers S, Nicholson R, Link T, Shemluck M, Yang J, Fricke ST, Novikoff PM, Papanikolaou A, Arnold A, Albanese C, Pestell R (July 2006). "Cyclin D1 determines mitochondrial function in vivo". Molecular and Cellular Biology. 26 (14): 5449–69. doi:10.1128/MCB.02074-05. PMC 1592725. PMID 16809779.
  14. ↑ 14.0 14.1 Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (May 1993). "Cyclin D1 is a nuclear protein required for cell cycle progression in G1". Genes & Development. 7 (5): 812–21. doi:10.1101/gad.7.5.812. PMID 8491378.
  15. ↑ Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ (October 1992). "Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins". Cell. 71 (2): 323–34. doi:10.1016/0092-8674(92)90360-o. PMID 1423597.
  16. ↑ 16.0 16.1 Diehl JA (2002). "Cycling to cancer with cyclin D1". Cancer Biology & Therapy. 1 (3): 226–31. doi:10.4161/cbt.72. PMID 12432268.
  17. ↑ 17.0 17.1 Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ (February 1997). "CDK-independent activation of estrogen receptor by cyclin D1". Cell. 88 (3): 405–15. doi:10.1016/S0092-8674(00)81879-6. PMID 9039267.
  18. ↑ Wang C, Li Z, Fu M, Bouras T, Pestell RG (2004). Signal transduction mediated by cyclin D1: from mitogens to cell proliferation: a molecular target with therapeutic potential. Cancer Treatment and Research. 119. pp. 217–37. doi:10.1007/1-4020-7847-1_11. ISBN 978-1-4020-7822-4. PMID 15164880.
  19. ↑ Fu M, Rao M, Bouras T, Wang C, Wu K, Zhang X, Li Z, Yao TP, Pestell RG (April 2005). "Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment". primary. The Journal of Biological Chemistry. 280 (17): 16934–41. doi:10.1074/jbc.m500403200. PMID 15713663.
  20. ↑ 20.0 20.1 20.2 Reutens AT, Fu M, Wang C, Albanese C, McPhaul MJ, Sun Z, Balk SP, Jänne OA, Palvimo JJ, Pestell RG (May 2001). "Cyclin D1 binds the androgen receptor and regulates hormone-dependent signaling in a p300/CBP-associated factor (P/CAF)-dependent manner". Molecular Endocrinology. 15 (5): 797–811. doi:10.1210/mend.15.5.0641. PMID 11328859.
  21. ↑ 21.0 21.1 Fu M, Wang C, Li Z, Sakamaki T, Pestell RG (December 2004). "Minireview: Cyclin D1: normal and abnormal functions". Endocrinology. 145 (12): 5439–47. doi:10.1210/en.2004-0959. PMID 15331580.
  22. ↑ McMahon C, Suthiphongchai T, DiRenzo J, Ewen ME (May 1999). "P/CAF associates with cyclin D1 and potentiates its activation of the estrogen receptor". Proceedings of the National Academy of Sciences of the United States of America. 96 (10): 5382–7. Bibcode:1999PNAS...96.5382M. doi:10.1073/pnas.96.10.5382. PMC 21868. PMID 10318892.
  23. ↑ 23.0 23.1 Fu M, Rao M, Bouras T, Wang C, Wu K, Zhang X, Li Z, Yao TP, Pestell RG (April 2005). "Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment". The Journal of Biological Chemistry. 280 (17): 16934–41. doi:10.1074/jbc.M500403200. PMID 15713663.
  24. ↑ Böhmer RM, Scharf E, Assoian RK (January 1996). "Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin D1". Molecular Biology of the Cell. 7 (1): 101–111. doi:10.1091/mbc.7.1.101. PMC 278616. PMID 8741843.
  25. ↑ Mittnacht S, Paterson H, Olson MF, Marshall CJ (March 1997). "Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein". Current Biology. 7 (3): 219–21. doi:10.1016/s0960-9822(97)70094-0. PMID 9395436.
  26. ↑ Mulcahy LS, Smith MR, Stacey DW (1985). "Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells". Nature. 313 (5999): 241–3. Bibcode:1985Natur.313..241M. doi:10.1038/313241a0. PMID 3918269.
  27. ↑ Peeper DS, Upton TM, Ladha MH, Neuman E, Zalvide J, Bernards R, DeCaprio JA, Ewen ME (March 1997). "Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein" (Submitted manuscript). Nature. 386 (6621): 177–81. Bibcode:1997Natur.386..177P. doi:10.1038/386177a0. PMID 9062190.
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