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Like all cyclin family members, cyclin E forms a complex with cyclin-dependent kinase (CDK2). Cyclin E/CDK2 regulates multiple cellular processes by phosphorylating numerous downstream proteins.
Like all cyclin family members, cyclin E forms a complex with cyclin-dependent kinase (CDK2). Cyclin E/CDK2 regulates multiple cellular processes by phosphorylating numerous downstream proteins.


Cyclin E/CDK2 plays a critical role in the G1 phase and in the G1-S phase transition. Cyclin E/CDK2 phosphorylates retinoblastoma protein (Rb) to promote G1 progression. Hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase.<ref>Hinds PW, Mittnacht S, Dulic V, et al. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell. 1992, 70: 993-1006</ref> Cyclin E/CDK2 also phosphorylates p27 and p21 during G1 and S phases, respectively. Smad3, a key mediator of TGF-β pathway which inhibits cell cycle progression, can be phosphorylated by cyclin E/CDK2. The phosphorylation of Smad3 by cyclin E/CDK2 inhibits its transcriptional activity and ultimately facilitates cell cycle progression.<ref>Cooley A, Zelivianski S, Jeruss JS. Impact of cyclin E overexpression on Smad3 activity in [[breast cancer]] cell lines. Cell Cycle. 2010, 9: 4900-4907</ref> CBP/p300 and E2F-5 are also substrates of cyclin E/CDK2. Phosphorylation of these two proteins stimulates the transcriptional events during cell cycle progression.<ref>Morris L, Allen KE, La Thangue NB. Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators. Nat. Cell Biol. 2000, 2: 232-239</ref> Cyclin E/CDK2 can phosphorylate p220(NPAT) to promote histone gene transcription during cell cycle progression.<ref>Ma T, Van Tine BA, Wei Y, et al. Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription. Genes Dev. 2000, 14: 2298-2313</ref>
Cyclin E/CDK2 plays a critical role in the G1 phase and in the G1-S phase transition. Cyclin E/CDK2 phosphorylates retinoblastoma protein (Rb) to promote G1 progression. Hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase.<ref name="pmid1388095">{{cite journal | vauthors = Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA | title = Regulation of retinoblastoma protein functions by ectopic expression of human cyclins | journal = Cell | volume = 70 | issue = 6 | pages = 993–1006 | date = September 1992 | pmid = 1388095 | doi = }}</ref> Cyclin E/CDK2 also phosphorylates p27 and p21 during G1 and S phases, respectively. Smad3, a key mediator of TGF-β pathway which inhibits cell cycle progression, can be phosphorylated by cyclin E/CDK2. The phosphorylation of Smad3 by cyclin E/CDK2 inhibits its transcriptional activity and ultimately facilitates cell cycle progression.<ref name="pmid21150326">{{cite journal | vauthors = Cooley A, Zelivianski S, Jeruss JS | title = Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines | journal = Cell Cycle (Georgetown, Tex.) | volume = 9 | issue = 24 | pages = 4900–7 | date = December 2010 | pmid = 21150326 | pmc = 3047813 | doi = 10.4161/cc.9.24.14158 }}</ref> CBP/p300 and E2F-5 are also substrates of cyclin E/CDK2. Phosphorylation of these two proteins stimulates the transcriptional events during cell cycle progression.<ref name="pmid10783242">{{cite journal | vauthors = Morris L, Allen KE, La Thangue NB | title = Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators | journal = Nature Cell Biology | volume = 2 | issue = 4 | pages = 232–9 | date = April 2000 | pmid = 10783242 | doi = 10.1038/35008660 }}</ref> Cyclin E/CDK2 can phosphorylate p220(NPAT) to promote histone gene transcription during cell cycle progression.<ref name="pmid10995387">{{cite journal | vauthors = Ma T, Van Tine BA, Wei Y, Garrett MD, Nelson D, Adams PD, Wang J, Qin J, Chow LT, Harper JW | title = Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription | journal = Genes & Development | volume = 14 | issue = 18 | pages = 2298–313 | date = September 2000 | pmid = 10995387 | pmc = 316935 | doi = }}</ref>


Apart from the function in cell cycle progression, cyclin E/CDK2 plays a role in the centrosome cycle. This function is performed by phosphorylating nucleophosmin (NPM). Then NPM is released from binding to an unduplicated centrosome, thereby triggering duplication.<ref>Okuda M, Horn HF, Tarapore P, et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication.  Cell 2000, 103: 127-140</ref> CP110 is another cyclin E/CDK2 substrate which involves in centriole duplication and centrosome separation.<ref>Chen Z, Indjeian VB, McManus M, et al. CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. Dev Cell. 2002, 3: 339-350</ref> Cyclin E/CDK2 has also been shown to regulate the apoptotic response to DNA damage via phosphorylation of FOXO1.<ref>Huang H, Regan KM, Lou Z, et al. Cdk2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science. 2006, 314: 294-297</ref>
Apart from the function in cell cycle progression, cyclin E/CDK2 plays a role in the centrosome cycle. This function is performed by phosphorylating nucleophosmin (NPM). Then NPM is released from binding to an unduplicated centrosome, thereby triggering duplication.<ref name="pmid11051553">{{cite journal | vauthors = Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan PK, Knudsen ES, Hofmann IA, Snyder JD, Bove KE, Fukasawa K | title = Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication | journal = Cell | volume = 103 | issue = 1 | pages = 127–40 | date = September 2000 | pmid = 11051553 | doi = }}</ref> CP110 is another cyclin E/CDK2 substrate which involves in centriole duplication and centrosome separation.<ref name="pmid12361598">{{cite journal | vauthors = Chen Z, Indjeian VB, McManus M, Wang L, Dynlacht BD | title = CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells | journal = Developmental Cell | volume = 3 | issue = 3 | pages = 339–50 | date = September 2002 | pmid = 12361598 | doi = }}</ref> Cyclin E/CDK2 has also been shown to regulate the apoptotic response to DNA damage via phosphorylation of FOXO1.<ref name="pmid17038621">{{cite journal | vauthors = Huang H, Regan KM, Lou Z, Chen J, Tindall DJ | title = CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage | journal = Science | volume = 314 | issue = 5797 | pages = 294–7 | date = October 2006 | pmid = 17038621 | doi = 10.1126/science.1130512 }}</ref>


==Cyclin E and Cancer==
==Cyclin E and Cancer==
Over-expression of cyclin E correlates with tumorigenesis. It is involved in various types of cancers, including breast, colon, bladder, skin and lung cancer.<ref>Donnellan R and Chetty R. Cyclin E in human cancers. FASEB J. 1999, 13: 773-780</ref> DNA copy-number amplification of cyclin E1 is involved in brain cancer.<ref>{{Cite journal
Over-expression of cyclin E correlates with tumorigenesis. It is involved in various types of cancers, including breast, colon, bladder, skin and lung cancer.<ref name="pmid10224221">{{cite journal | vauthors = Donnellan R, Chetty R | title = Cyclin E in human cancers | journal = FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology | volume = 13 | issue = 8 | pages = 773–80 | date = May 1999 | pmid = 10224221 | doi = }}</ref> DNA copy-number amplification of cyclin E1 is involved in brain cancer.<ref>{{cite journal | vauthors = Lee CH, Alpert BO, Sankaranarayanan P, Alter O | title = GSVD comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival | journal = PLOS One | volume = 7 | issue = 1 | pages = e30098 | date = January 2012 | pmid = 22291905 | doi = 10.1371/journal.pone.0030098 }}</ref><ref>{{cite journal | vauthors = Aiello KA, Alter O | title = Platform-Independent Genome-Wide Pattern of DNA Copy-Number Alterations Predicting Astrocytoma Survival and Response to Treatment Revealed by the GSVD Formulated as a Comparative Spectral Decomposition | journal = PLOS One | volume = 11 | issue = 10 | pages = e0164546 | date = October 2016 | pmid = 27798635 | doi = 10.1371/journal.pone.0164546 }}</ref> Besides that, dysregulated cyclin E activity causes cell lineage-specific abnormalities, such as impaired maturation due to increased cell proliferation and apoptosis or senescence.<ref name="pmid18559482">{{cite journal | vauthors = Minella AC, Loeb KR, Knecht A, Welcker M, Varnum-Finney BJ, Bernstein ID, Roberts JM, Clurman BE | title = Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo | journal = Genes & Development | volume = 22 | issue = 12 | pages = 1677–89 | date = June 2008 | pmid = 18559482 | pmc = 2428064 | doi = 10.1101/gad.1650208 }}</ref><ref name="pmid20978349">{{cite journal | vauthors = Kossatz U, Breuhahn K, Wolf B, Hardtke-Wolenski M, Wilkens L, Steinemann D, Singer S, Brass F, Kubicka S, Schlegelberger B, Schirmacher P, Manns MP, Singer JD, Malek NP | title = The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells | journal = The Journal of Clinical Investigation | volume = 120 | issue = 11 | pages = 3820–33 | date = November 2010 | pmid = 20978349 | pmc = 2964969 | doi = 10.1172/JCI41959 | url = https://infoscience.epfl.ch/record/182087/files/JCI41959.pdf }}</ref>
| author1 = C. H. Lee* | author2 = B. O. Alpert* | author3 = P. Sankaranarayanan | author4 = O. Alter | title = GSVD Comparison of Patient-Matched Normal and Tumor aCGH Profiles Reveals Global Copy-Number Alterations Predicting Glioblastoma Multiforme Survival
| journal = PLOS ONE
| volume = 7
| issue = 1
| pages = e30098
| date = January 2012
| doi = 10.1371/journal.pone.0030098
| url = https://dx.doi.org/10.1371/journal.pone.0030098
| id = [http://www.alterlab.org/research/highlights/pone.0030098_Highlight.pdf Highlight]
}}</ref><ref>{{Cite journal
| author1 = K. A. Aiello | author2 = O. Alter | title = Platform-Independent Genome-Wide Pattern of DNA Copy-Number Alterations Predicting Astrocytoma Survival and Response to Treatment Revealed by the GSVD Formulated as a Comparative Spectral Decomposition
| journal = PLOS ONE
| volume = 11
| issue = 10
| pages = e0164546
| date = October 2016
| doi = 10.1371/journal.pone.0164546
| url = https://dx.doi.org/10.1371/journal.pone.0164546
}}</ref> Besides that, dysregulated cyclin E activity causes cell lineage-specific abnormalities, such as impaired maturation due to increased cell proliferation and apoptosis or senescence.<ref>Minella AC, Loeb KR, Knecht A, et al. Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo. Genes Dev. 2008, 22: 1677-1689</ref><ref>Kossatz U, Breuhahn K, Wolf B, et al. The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells. J Clin Invest. 2010, 120: 3820-3833</ref>


Several mechanisms lead to the deregulated expression of cyclin E. In most cases, gene amplification causes the overexpression.<ref>Geisen C, Moroy T. The oncogenic activity of cyclin E is not confirmed to Cdk2 activation alone but relies on several other, distinct functions of the protein. J Biol Chem. 2002, 277: 39909-39918</ref> Proteosome caused defected degradation is another mechanism. Loss-of-function mutations of FBXW7 were found in several cancer cells. FBXW7 encodes F-box proteins which target cyclin E for ubiquitination.<ref>Buckley MF, Sweeney KJ, Hamilton JA, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993, 8: 2127-2133</ref> Cyclin E overexpression can lead to G1 shortening, decrease in cell size or loss of serum requirement for proliferation.
Several mechanisms lead to the deregulated expression of cyclin E. In most cases, gene amplification causes the overexpression.<ref name="pmid12149264">{{cite journal | vauthors = Geisen C, Moroy T | title = The oncogenic activity of cyclin E is not confined to Cdk2 activation alone but relies on several other, distinct functions of the protein | journal = The Journal of Biological Chemistry | volume = 277 | issue = 42 | pages = 39909–18 | date = October 2002 | pmid = 12149264 | doi = 10.1074/jbc.M205919200 }}</ref> Proteosome caused defected degradation is another mechanism. Loss-of-function mutations of FBXW7 were found in several cancer cells. FBXW7 encodes F-box proteins which target cyclin E for ubiquitination.<ref name="pmid8336939">{{cite journal | vauthors = Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CK, Musgrove EA, Sutherland RL | title = Expression and amplification of cyclin genes in human breast cancer | journal = Oncogene | volume = 8 | issue = 8 | pages = 2127–33 | date = August 1993 | pmid = 8336939 | doi = }}</ref> Cyclin E overexpression can lead to G1 shortening, decrease in cell size or loss of serum requirement for proliferation.


Dysregulation of cyclin E occurs in 18-22% of the breast cancers. Cyclin E is a prognostic marker in breast cancer, its altered expression increased with the increasing stage and grade of the tumor.<ref>Keyomarsi K, O’Leary N, Molnar G, et al. Cyclin E, a potential prognostic marker for breast cancer. Cancer Research. 1994. 54: 380-385.</ref> Low molecular weight cyclin E isoforms have been shown to be of great pathogenetic and prognostic importance for breast cancer.<ref>Wingate H, Puskas A, Duong M, et al. Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression. Cell Cycle. 2009, 8: 1062-1068</ref> These isoforms are resistant to CKIs, bind with CDK2 more efficiently and can stimulate the cell cycle progression more efficiently. They are proved to be a remarkable marker of the prognosis of early-stage-node negative breast cancer.<ref>Keyomarsi K, Tucker SL, Buchholz TA, et al. Cyclin E and survival in patients with breast cancer. NEJM 2002, 347: 1566-1575</ref> Importantly, a recent research pointed out cyclin E overexpression is a mechanism of Trastuzumab resistance in HER2+ breast cancer patients. Thus, co-treatment of trastuzumab with CDK2 inhibitors may be a valid strategy.<ref>Scaltriti M, Eichhorn PJ, Cortes J, et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. PNAS. 2011, 108: 3761-3766</ref>
Dysregulation of cyclin E occurs in 18-22% of the breast cancers. Cyclin E is a prognostic marker in breast cancer, its altered expression increased with the increasing stage and grade of the tumor.<ref name="pmid7903908">{{cite journal | vauthors = Keyomarsi K, O'Leary N, Molnar G, Lees E, Fingert HJ, Pardee AB | title = Cyclin E, a potential prognostic marker for breast cancer | journal = Cancer Research | volume = 54 | issue = 2 | pages = 380–5 | date = January 1994 | pmid = 7903908 | doi = }}</ref> Low molecular weight cyclin E isoforms have been shown to be of great pathogenetic and prognostic importance for breast cancer.<ref name="pmid19305161">{{cite journal | vauthors = Wingate H, Puskas A, Duong M, Bui T, Richardson D, Liu Y, Tucker SL, Van Pelt C, Meijer L, Hunt K, Keyomarsi K | title = Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression | journal = Cell Cycle (Georgetown, Tex.) | volume = 8 | issue = 7 | pages = 1062–8 | date = April 2009 | pmid = 19305161 | pmc = 2692060 | doi = 10.4161/cc.8.7.8119 }}</ref> These isoforms are resistant to CKIs, bind with CDK2 more efficiently and can stimulate the cell cycle progression more efficiently. They are proved to be a remarkable marker of the prognosis of early-stage-node negative breast cancer.<ref name="pmid12432040">{{cite journal | vauthors = Sutherland RL, Musgrove EA | title = Cyclin E and prognosis in patients with breast cancer | journal = The New England Journal of Medicine | volume = 347 | issue = 20 | pages = 1546–7 | date = November 2002 | pmid = 12432040 | doi = 10.1056/NEJMNEJMp020124 }}</ref> Importantly, a recent research pointed out cyclin E overexpression is a mechanism of Trastuzumab resistance in HER2+ breast cancer patients. Thus, co-treatment of trastuzumab with CDK2 inhibitors may be a valid strategy.<ref name="pmid21321214">{{cite journal | vauthors = Scaltriti M, Eichhorn PJ, Cortés J, Prudkin L, Aura C, Jiménez J, Chandarlapaty S, Serra V, Prat A, Ibrahim YH, Guzmán M, Gili M, Rodríguez O, Rodríguez S, Pérez J, Green SR, Mai S, Rosen N, Hudis C, Baselga J | display-authors = 6 | title = Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 9 | pages = 3761–6 | date = March 2011 | pmid = 21321214 | pmc = 3048107 | doi = 10.1073/pnas.1014835108 }}</ref>


Cyclin E overexpression is implicated in carcinomas at various sites along the gastrointestinal tract. Among these carcinomas, cyclin E appears to be more important in stomach and colon cancer. Cyclin E overexpression was found in 50-60% of gastric adenomas and adenocarcinomas.<ref>Yasui W, Akama Y, Kuniyasu H, Yokozaki H, et al. Expression of cyclin E in human gastric adenomas and adenocarcinomas: correlation with proliferative activity and p53 status. Exp Ther Oncol. 1996, 1: 88-94</ref> In ~10% of colorectal carcinomas, cyclin E gene amplification is found, sometimes together with CDK2 gene amplification.<ref>Kitahara K, Yasui W, Kuniyasu H, et al. Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas. Int. J. Cancer. 1995, 62: 25-28</ref>
Cyclin E overexpression is implicated in carcinomas at various sites along the gastrointestinal tract. Among these carcinomas, cyclin E appears to be more important in stomach and colon cancer. Cyclin E overexpression was found in 50-60% of gastric adenomas and adenocarcinomas.<ref name="pmid9414392">{{cite journal | vauthors = Yasui W, Akama Y, Kuniyasu H, Yokozaki H, Semba S, Shimamoto F, Tahara E | title = Expression of cyclin E in human gastric adenomas and adenocarcinomas: correlation with proliferative activity and p53 status | journal = Journal of Experimental Therapeutics & Oncology | volume = 1 | issue = 2 | pages = 88–94 | date = March 1996 | pmid = 9414392 | doi = }}</ref> In ~10% of colorectal carcinomas, cyclin E gene amplification is found, sometimes together with CDK2 gene amplification.<ref name="pmid7601562">{{cite journal | vauthors = Kitahara K, Yasui W, Kuniyasu H, Yokozaki H, Akama Y, Yunotani S, Hisatsugu T, Tahara E | title = Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas | journal = International Journal of Cancer | volume = 62 | issue = 1 | pages = 25–8 | date = July 1995 | pmid = 7601562 | doi = }}</ref>


Cyclin E is also a useful prognostic marker for lung cancer. There is significant association between cyclin E over-expression and the prognosis of lung cancer. It is believed increased expression of cyclin E correlated with poorer prognosis.<ref>Huang L, Wang D, Chen Y, et al. Meta-analysis for cyclin E in lung cancer survival. Clinica Chimica Acta. 2012, 413: 663-668</ref>
Cyclin E is also a useful prognostic marker for lung cancer. There is significant association between cyclin E over-expression and the prognosis of lung cancer. It is believed increased expression of cyclin E correlated with poorer prognosis.<ref name="pmid22244930">{{cite journal | vauthors = Huang LN, Wang DS, Chen YQ, Li W, Hu FD, Gong BL, Zhao CL, Jia W | title = Meta-analysis for cyclin E in lung cancer survival | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 413 | issue = 7-8 | pages = 663–8 | date = April 2012 | pmid = 22244930 | doi = 10.1016/j.cca.2011.12.020 }}</ref>


==References==
==References==

Revision as of 15:51, 31 October 2018

cyclin E1
Identifiers
SymbolCCNE1
Alt. symbolsCCNE
Entrez898
HUGO1589
OMIM123837
RefSeqNM_001238
UniProtP24864
Other data
LocusChr. 19 q12
cyclin E2
Identifiers
SymbolCCNE2
Entrez9134
HUGO1590
OMIM603775
RefSeqNM_057749
UniProtO96020
Other data
LocusChr. 8 q22.1

Cyclin E is a member of the cyclin family.

Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphorylates p27Kip1 (an inhibitor of Cyclin D), tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase.

Expression of cyclins through the cell cycle.
Expression of cyclins through the cell cycle.

Functions of Cyclin E

Like all cyclin family members, cyclin E forms a complex with cyclin-dependent kinase (CDK2). Cyclin E/CDK2 regulates multiple cellular processes by phosphorylating numerous downstream proteins.

Cyclin E/CDK2 plays a critical role in the G1 phase and in the G1-S phase transition. Cyclin E/CDK2 phosphorylates retinoblastoma protein (Rb) to promote G1 progression. Hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase.[1] Cyclin E/CDK2 also phosphorylates p27 and p21 during G1 and S phases, respectively. Smad3, a key mediator of TGF-β pathway which inhibits cell cycle progression, can be phosphorylated by cyclin E/CDK2. The phosphorylation of Smad3 by cyclin E/CDK2 inhibits its transcriptional activity and ultimately facilitates cell cycle progression.[2] CBP/p300 and E2F-5 are also substrates of cyclin E/CDK2. Phosphorylation of these two proteins stimulates the transcriptional events during cell cycle progression.[3] Cyclin E/CDK2 can phosphorylate p220(NPAT) to promote histone gene transcription during cell cycle progression.[4]

Apart from the function in cell cycle progression, cyclin E/CDK2 plays a role in the centrosome cycle. This function is performed by phosphorylating nucleophosmin (NPM). Then NPM is released from binding to an unduplicated centrosome, thereby triggering duplication.[5] CP110 is another cyclin E/CDK2 substrate which involves in centriole duplication and centrosome separation.[6] Cyclin E/CDK2 has also been shown to regulate the apoptotic response to DNA damage via phosphorylation of FOXO1.[7]

Cyclin E and Cancer

Over-expression of cyclin E correlates with tumorigenesis. It is involved in various types of cancers, including breast, colon, bladder, skin and lung cancer.[8] DNA copy-number amplification of cyclin E1 is involved in brain cancer.[9][10] Besides that, dysregulated cyclin E activity causes cell lineage-specific abnormalities, such as impaired maturation due to increased cell proliferation and apoptosis or senescence.[11][12]

Several mechanisms lead to the deregulated expression of cyclin E. In most cases, gene amplification causes the overexpression.[13] Proteosome caused defected degradation is another mechanism. Loss-of-function mutations of FBXW7 were found in several cancer cells. FBXW7 encodes F-box proteins which target cyclin E for ubiquitination.[14] Cyclin E overexpression can lead to G1 shortening, decrease in cell size or loss of serum requirement for proliferation.

Dysregulation of cyclin E occurs in 18-22% of the breast cancers. Cyclin E is a prognostic marker in breast cancer, its altered expression increased with the increasing stage and grade of the tumor.[15] Low molecular weight cyclin E isoforms have been shown to be of great pathogenetic and prognostic importance for breast cancer.[16] These isoforms are resistant to CKIs, bind with CDK2 more efficiently and can stimulate the cell cycle progression more efficiently. They are proved to be a remarkable marker of the prognosis of early-stage-node negative breast cancer.[17] Importantly, a recent research pointed out cyclin E overexpression is a mechanism of Trastuzumab resistance in HER2+ breast cancer patients. Thus, co-treatment of trastuzumab with CDK2 inhibitors may be a valid strategy.[18]

Cyclin E overexpression is implicated in carcinomas at various sites along the gastrointestinal tract. Among these carcinomas, cyclin E appears to be more important in stomach and colon cancer. Cyclin E overexpression was found in 50-60% of gastric adenomas and adenocarcinomas.[19] In ~10% of colorectal carcinomas, cyclin E gene amplification is found, sometimes together with CDK2 gene amplification.[20]

Cyclin E is also a useful prognostic marker for lung cancer. There is significant association between cyclin E over-expression and the prognosis of lung cancer. It is believed increased expression of cyclin E correlated with poorer prognosis.[21]

References

  1. ↑ Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA (September 1992). "Regulation of retinoblastoma protein functions by ectopic expression of human cyclins". Cell. 70 (6): 993–1006. PMID 1388095.
  2. ↑ Cooley A, Zelivianski S, Jeruss JS (December 2010). "Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines". Cell Cycle (Georgetown, Tex.). 9 (24): 4900–7. doi:10.4161/cc.9.24.14158. PMC 3047813. PMID 21150326.
  3. ↑ Morris L, Allen KE, La Thangue NB (April 2000). "Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators". Nature Cell Biology. 2 (4): 232–9. doi:10.1038/35008660. PMID 10783242.
  4. ↑ Ma T, Van Tine BA, Wei Y, Garrett MD, Nelson D, Adams PD, Wang J, Qin J, Chow LT, Harper JW (September 2000). "Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription". Genes & Development. 14 (18): 2298–313. PMC 316935. PMID 10995387.
  5. ↑ Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan PK, Knudsen ES, Hofmann IA, Snyder JD, Bove KE, Fukasawa K (September 2000). "Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication". Cell. 103 (1): 127–40. PMID 11051553.
  6. ↑ Chen Z, Indjeian VB, McManus M, Wang L, Dynlacht BD (September 2002). "CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells". Developmental Cell. 3 (3): 339–50. PMID 12361598.
  7. ↑ Huang H, Regan KM, Lou Z, Chen J, Tindall DJ (October 2006). "CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage". Science. 314 (5797): 294–7. doi:10.1126/science.1130512. PMID 17038621.
  8. ↑ Donnellan R, Chetty R (May 1999). "Cyclin E in human cancers". FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 13 (8): 773–80. PMID 10224221.
  9. ↑ Lee CH, Alpert BO, Sankaranarayanan P, Alter O (January 2012). "GSVD comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival". PLOS One. 7 (1): e30098. doi:10.1371/journal.pone.0030098. PMID 22291905.
  10. ↑ Aiello KA, Alter O (October 2016). "Platform-Independent Genome-Wide Pattern of DNA Copy-Number Alterations Predicting Astrocytoma Survival and Response to Treatment Revealed by the GSVD Formulated as a Comparative Spectral Decomposition". PLOS One. 11 (10): e0164546. doi:10.1371/journal.pone.0164546. PMID 27798635.
  11. ↑ Minella AC, Loeb KR, Knecht A, Welcker M, Varnum-Finney BJ, Bernstein ID, Roberts JM, Clurman BE (June 2008). "Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo". Genes & Development. 22 (12): 1677–89. doi:10.1101/gad.1650208. PMC 2428064. PMID 18559482.
  12. ↑ Kossatz U, Breuhahn K, Wolf B, Hardtke-Wolenski M, Wilkens L, Steinemann D, Singer S, Brass F, Kubicka S, Schlegelberger B, Schirmacher P, Manns MP, Singer JD, Malek NP (November 2010). "The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells" (PDF). The Journal of Clinical Investigation. 120 (11): 3820–33. doi:10.1172/JCI41959. PMC 2964969. PMID 20978349.
  13. ↑ Geisen C, Moroy T (October 2002). "The oncogenic activity of cyclin E is not confined to Cdk2 activation alone but relies on several other, distinct functions of the protein". The Journal of Biological Chemistry. 277 (42): 39909–18. doi:10.1074/jbc.M205919200. PMID 12149264.
  14. ↑ Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CK, Musgrove EA, Sutherland RL (August 1993). "Expression and amplification of cyclin genes in human breast cancer". Oncogene. 8 (8): 2127–33. PMID 8336939.
  15. ↑ Keyomarsi K, O'Leary N, Molnar G, Lees E, Fingert HJ, Pardee AB (January 1994). "Cyclin E, a potential prognostic marker for breast cancer". Cancer Research. 54 (2): 380–5. PMID 7903908.
  16. ↑ Wingate H, Puskas A, Duong M, Bui T, Richardson D, Liu Y, Tucker SL, Van Pelt C, Meijer L, Hunt K, Keyomarsi K (April 2009). "Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression". Cell Cycle (Georgetown, Tex.). 8 (7): 1062–8. doi:10.4161/cc.8.7.8119. PMC 2692060. PMID 19305161.
  17. ↑ Sutherland RL, Musgrove EA (November 2002). "Cyclin E and prognosis in patients with breast cancer". The New England Journal of Medicine. 347 (20): 1546–7. doi:10.1056/NEJMNEJMp020124. PMID 12432040.
  18. ↑ Scaltriti M, Eichhorn PJ, Cortés J, Prudkin L, Aura C, Jiménez J, et al. (March 2011). "Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients". Proceedings of the National Academy of Sciences of the United States of America. 108 (9): 3761–6. doi:10.1073/pnas.1014835108. PMC 3048107. PMID 21321214.
  19. ↑ Yasui W, Akama Y, Kuniyasu H, Yokozaki H, Semba S, Shimamoto F, Tahara E (March 1996). "Expression of cyclin E in human gastric adenomas and adenocarcinomas: correlation with proliferative activity and p53 status". Journal of Experimental Therapeutics & Oncology. 1 (2): 88–94. PMID 9414392.
  20. ↑ Kitahara K, Yasui W, Kuniyasu H, Yokozaki H, Akama Y, Yunotani S, Hisatsugu T, Tahara E (July 1995). "Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas". International Journal of Cancer. 62 (1): 25–8. PMID 7601562.
  21. ↑ Huang LN, Wang DS, Chen YQ, Li W, Hu FD, Gong BL, Zhao CL, Jia W (April 2012). "Meta-analysis for cyclin E in lung cancer survival". Clinica Chimica Acta; International Journal of Clinical Chemistry. 413 (7–8): 663–8. doi:10.1016/j.cca.2011.12.020. PMID 22244930.

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