ZC3HC1: Difference between revisions

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{{Infobox_gene}}
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'''Nuclear-interacting partner of ALK''' (NIPA)''',''' also known as zinc finger C3HC-type protein 1 (ZC3HC1), is a [[protein]] that in humans is encoded by the ''ZC3HC1'' [[gene]] on [[Chromosome 7 (human)|chromosome 7]].<ref name="pmid11042152">{{cite journal | vauthors = Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z | title = Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells | journal = Genome Research | volume = 10 | issue = 10 | pages = 1546–60 | date = October 2000 | pmid = 11042152 | pmc = 310934 | doi = 10.1101/gr.140200 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ZC3HC1 zinc finger, C3HC-type containing 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51530| accessdate = }}</ref> It is ubiquitously expressed in many tissues and cell types though exclusively expressed in the [[Nucleus (cell)|nuclear]] [[subcellular location]].<ref>{{Cite web|url=http://biogps.org/#goto=genereport&id=51530|title=BioGPS - your Gene Portal System|website=biogps.org|access-date=2016-10-11}}</ref><ref name="pmid16009132"/> NIPA is a skp1 [[cullin]] [[F-box protein|F-box]] (SCF)-type [[E3 ligase|ubiquitin E3 ligase]] (SCFNIPA) complex protein involved in regulating entry into [[mitosis]].<ref name="pmid17389604"/> The ''ZC3HC1'' gene also contains one of 27 [[SNPs]] associated with increased risk of [[coronary artery disease]].<ref name="ReferenceA">{{cite journal | vauthors = Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS | title = Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials | journal = Lancet | volume = 385 | issue = 9984 | pages = 2264–71 | date = June 2015 | pmid = 25748612 | doi = 10.1016/S0140-6736(14)61730-X | pmc=4608367}}</ref>
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| update_protein_box = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = Zinc finger, C3HC-type containing 1
| HGNCid = 29913
| Symbol = ZC3HC1
| AltSymbols =; 1110054L24Rik; HSPC216; NIPA
| OMIM = 
| ECnumber = 
| Homologene = 32315
| MGIid = 1916023
| Function = {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0019901 |text = protein kinase binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006512 |text = ubiquitin cycle}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007067 |text = mitosis}} {{GNF_GO|id=GO:0051301 |text = cell division}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 51530
    | Hs_Ensembl = ENSG00000091732
    | Hs_RefseqProtein = NP_057562
    | Hs_RefseqmRNA = NM_016478
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 7
    | Hs_GenLoc_start = 129445363
    | Hs_GenLoc_end = 129478469
    | Hs_Uniprot = Q86WB0
    | Mm_EntrezGene = 232679
    | Mm_Ensembl = ENSMUSG00000039130
    | Mm_RefseqmRNA = NM_172735
    | Mm_RefseqProtein = NP_766323
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 6
    | Mm_GenLoc_start = 30316398
    | Mm_GenLoc_end = 30341038
    | Mm_Uniprot = Q3TI64
  }}
}}
'''Zinc finger, C3HC-type containing 1''', also known as '''ZC3HC1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: ZC3HC1 zinc finger, C3HC-type containing 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51530| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
=== Gene ===
{{PBB_Summary
The ''ZC3HC1'' gene resides on chromosome 7 at the band 7q32.2 and includes 14 [[exon]]s.<ref name="entrez" />
| section_title =
| summary_text =
}}


==References==
=== Protein ===
{{reflist|2}}
NIPA is a 60-kDa E3 ligase that contains one C3HC-type [[zinc finger]] and one F-box-like region.<ref name="pmid12748172">{{cite journal | vauthors = Ouyang T, Bai RY, Bassermann F, von Klitzing C, Klumpen S, Miething C, Morris SW, Peschel C, Duyster J | title = Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA) | journal = The Journal of Biological Chemistry | volume = 278 | issue = 32 | pages = 30028–36 | date = August 2003 | pmid = 12748172 | doi = 10.1074/jbc.M300883200 }}</ref><ref name="ReferenceB">{{cite journal | vauthors = Kunnas T, Nikkari ST | title = Association of Zinc Finger, C3HC-Type Containing 1 (ZC3HC1) rs11556924 Genetic Variant With Hypertension in a Finnish Population, the TAMRISK Study | journal = Medicine | volume = 94 | issue = 32 | pages = e1221 | date = August 2015 | pmid = 26266351 | doi = 10.1097/MD.0000000000001221 | pmc=4616712}}</ref><ref name="ReferenceB"/><ref>{{Cite web|url=https://www.uniprot.org/uniprot/Q86WB0|title=ZC3HC1 - Nuclear-interacting partner of ALK - Homo sapiens (Human) - ZC3HC1 gene & protein|website=www.uniprot.org|access-date=2016-10-11}}</ref> Moreover, a 50-[[Amino acid|residue]] region (amino acids 352-402) at its [[C-terminus|C-terminal]] serves as the [[Nuclear Localization Signal|nuclear translocation signal]] (NLS sequence) while a 96-residue region (amino acids 306-402) is proposed to serve as the [[phosphotyrosine-binding domain]].<ref name="pmid17389604">{{cite journal | vauthors = Bassermann F, von Klitzing C, Illert AL, Münch S, Morris SW, Pagano M, Peschel C, Duyster J | title = Multisite phosphorylation of nuclear interaction partner of ALK (NIPA) at G2/M involves cyclin B1/Cdk1 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 22 | pages = 15965–72 | date = June 2007 | pmid = 17389604 | doi = 10.1074/jbc.M610819200 }}</ref><ref name="pmid12748172"/> NIPA is one component of the nuclear SCFNIPA complex, and phosphorylation of NIPA at three serine residues, Ser-354, Ser-359 and Ser-395, has been demonstrated to inactivate the complex as a whole.<ref name="pmid17389604"/>
==Further reading==
 
{{refbegin | 2}}
== Function ==
{{PBB_Further_reading
 
| citations =  
NIPA is broadly expressed in the human tissues, with the highest expression in heart, skeletal muscle, and testis.<ref name="pmid12748172"/> It is a human F-box protein that defines an [[SCF complex|SCF]]-type [[ubiquitin]] [[E3]] ligase, the formation of which is regulated by cell-cycle-dependent phosphorylation of NIPA. [[Cyclin B1]], essential in the entry into [[mitosis]], is targeted by SCFNIPA in interphase. Phosphorylation of NIPA occurs in [[G2 phase]], results in dissociation of NIPA from the SCF core, and has been proven critical for proper G2/M transition.<ref name="pmid16009132">{{cite journal | vauthors = Bassermann F, von Klitzing C, Münch S, Bai RY, Kawaguchi H, Morris SW, Peschel C, Duyster J | title = NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry | journal = Cell | volume = 122 | issue = 1 | pages = 45–57 | date = July 2005 | pmid = 16009132 | doi = 10.1016/j.cell.2005.04.034 }}</ref>  Oscillating [[ubiquitination]] of nuclear cyclin B1 driven by the SCFNIPA complex contributes to the timing of mitotic entry.<ref name="pmid17389604"/><ref name="pmid16258267">{{cite journal | vauthors = Bassermann F, Peschel C, Duyster J | title = Mitotic entry: a matter of oscillating destruction | journal = Cell Cycle | volume = 4 | issue = 11 | pages = 1515–7 | date = November 2005 | pmid = 16258267 | doi = 10.4161/cc.4.11.2192 }}</ref> NIPA is also reported to delay [[apoptosis]] and the localization of NIPA is required for this antiapoptotic function.<ref name="pmid12748172"/>
*{{cite journal | author=Dias Neto E, Correa RG, Verjovski-Almeida S, ''et al.'' |title=Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 7 |pages= 3491-6 |year= 2000 |pmid= 10737800 |doi= }}
 
*{{cite journal  | author=Zhang QH, Ye M, Wu XY, ''et al.'' |title=Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells. |journal=Genome Res. |volume=10 |issue= 10 |pages= 1546-60 |year= 2001 |pmid= 11042152 |doi=  }}
== Model organisms ==
*{{cite journal | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788-95 |year= 2001 |pmid= 11076863 |doi= }}
 
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: right;" |
*{{cite journal | author=Ouyang T, Bai RY, Bassermann F, ''et al.'' |title=Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA). |journal=J. Biol. Chem. |volume=278 |issue= 32 |pages= 30028-36 |year= 2003 |pmid= 12748172 |doi= 10.1074/jbc.M300883200 }}
|+ ''Zc3hc1'' knockout mouse phenotype
*{{cite journal | author=Hillier LW, Fulton RS, Fulton LA, ''et al.'' |title=The DNA sequence of human chromosome 7. |journal=Nature |volume=424 |issue= 6945 |pages= 157-64 |year= 2003 |pmid= 12853948 |doi= 10.1038/nature01782 }}
|-
*{{cite journal  | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
! Characteristic!! Phenotype
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
 
*{{cite journal  | author=Wiemann S, Arlt D, Huber W, ''et al.'' |title=From ORFeome to biology: a functional genomics pipeline. |journal=Genome Res. |volume=14 |issue= 10B |pages= 2136-44 |year= 2004 |pmid= 15489336 |doi= 10.1101/gr.2576704 }}
|-
*{{cite journal  | author=Bassermann F, von Klitzing C, Münch S, ''et al.'' |title=NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry. |journal=Cell |volume=122 |issue= 1 |pages= 45-57 |year= 2005 |pmid= 16009132 |doi= 10.1016/j.cell.2005.04.034 }}
| [[Homozygote]] viability || bgcolor="#C40000"|Abnormal
*{{cite journal  | author=Ambrogio C, Voena C, Manazza AD, ''et al.'' |title=p130Cas mediates the transforming properties of the anaplastic lymphoma kinase. |journal=Blood |volume=106 |issue= 12 |pages= 3907-16 |year= 2006 |pmid= 16105984 |doi= 10.1182/blood-2005-03-1204 }}
|-
*{{cite journal  | author=Mehrle A, Rosenfelder H, Schupp I, ''et al.'' |title=The LIFEdb database in 2006. |journal=Nucleic Acids Res. |volume=34 |issue= Database issue |pages= D415-8 |year= 2006 |pmid= 16381901 |doi= 10.1093/nar/gkj139 }}
| [[Recessive]] lethal study || bgcolor="#488ED3"|Normal
*{{cite journal  | author=Beausoleil SA, Villén J, Gerber SA, ''et al.'' |title=A probability-based approach for high-throughput protein phosphorylation analysis and site localization. |journal=Nat. Biotechnol. |volume=24 |issue= 10 |pages= 1285-92 |year= 2006 |pmid= 16964243 |doi= 10.1038/nbt1240 }}
|-
*{{cite journal  | author=Olsen JV, Blagoev B, Gnad F, ''et al.'' |title=Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. |journal=Cell |volume=127 |issue= 3 |pages= 635-48 |year= 2006 |pmid= 17081983 |doi= 10.1016/j.cell.2006.09.026 }}
| Homozygous Fertility || bgcolor="#C40000"|Abnormal
}}
|-
| Body weight || bgcolor="#C40000"|Abnormal<ref name="Body weight">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/weight-curves/ |title=Body weight data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Open Field (animal test)|Anxiety]] || bgcolor="#C40000"|Abnormal<ref name="Anxiety">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/open-field/ |title=Anxiety data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| Neurological assessment || bgcolor="#C40000"|Abnormal<ref name="Neurological assessment">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/neurological-assessment/ |title=Neurological assessment data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| Grip strength || bgcolor="#488ED3"|Normal
|-
| [[Hot plate test|Hot plate]] || bgcolor="#488ED3"|Normal
|-
| [[Dysmorphology]] || bgcolor="#C40000"|Abnormal<ref name="Dysmorphology">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/dysmorphology/ |title=Dysmorphology data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Indirect calorimetry]] || bgcolor="#C40000"|Abnormal<ref name="Indirect calorimetry">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/indirect-calorimetry/ |title=Indirect calorimetry data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Glucose tolerance test]] || bgcolor="#488ED3"|Normal
|-
| [[Auditory brainstem response]] || bgcolor="#488ED3"|Normal
|-
| [[Dual-energy X-ray absorptiometry|DEXA]] || bgcolor="#C40000"|Abnormal<ref name="DEXA">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/body-composition-dexa/ |title=DEXA data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Radiography]] || bgcolor="#C40000"|Abnormal<ref name="Radiography">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/x-ray-imaging/ |title=Radiography data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| Body temperature || bgcolor="#488ED3"|Normal
|-
| Eye morphology || bgcolor="#488ED3"|Normal
|-
| [[Clinical chemistry]] || bgcolor="#488ED3"|Normal
|-
| [[Haematology]] || bgcolor="#C40000"|Abnormal<ref name="Haematology">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/haematology-cbc/ |title=Haematology data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Peripheral blood lymphocyte]]s || bgcolor="#C40000"|Abnormal<ref name="Peripheral blood lymphocytes">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/peripheral-blood-lymphocytes/ |title=Peripheral blood lymphocytes data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| Heart weight || bgcolor="#488ED3"|Normal
|-
| ''[[Salmonella]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Salmonella'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/salmonella-challenge/ |title=''Salmonella'' infection data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| ''[[Citrobacter]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Citrobacter'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBGD/citrobacter-challenge/ |title=''Citrobacter'' infection data for Zc3hc1 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| colspan=2; style="text-align: center;" | All tests and analysis from<ref name="mgp_reference">{{cite journal | doi = 10.1111/j.1755-3768.2010.4142.x | title = The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice | year = 2010 | author = Gerdin AK | journal = Acta Ophthalmologica | volume = 88 | pages =  925–7 }}</ref><ref>[http://www.sanger.ac.uk/mouseportal/ Mouse Resources Portal], Wellcome Trust Sanger Institute.</ref>
|}
[[Model organism]]s have been used in the study of ZC3HC1 function. A conditional [[knockout mouse]] line, called ''Zc3hc1<sup>tm1a(KOMP)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Zc3hc1 |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4362278 |title=Mouse Genome Informatics}}</ref> was generated as part of the [[International Knockout Mouse Consortium]] program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref>
 
Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biology | volume = 12 | issue = 6 | pages = 224 | year = 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}</ref> Twenty two tests were carried out on [[mutant]] mice and eleven significant abnormalities were observed.<ref name="mgp_reference" /> Fewer than expected [[homozygous]] [[mutant]] mice were identified at [[weaning]]. Mutants appear to be subfertile, had decreased vertical activity in an open field, decreased lean body mass, decreased rib number and decreased mature [[B cell]] number. Males also had a decreased body weight, an abnormal posture and atypical [[indirect calorimetry]] data. Females also had an abnormally short snout and atypical haematology parameters .<ref name="mgp_reference" />
{{clear}}
 
== Clinical relevance ==
In humans, NIPA has been implicated in cardiovascular diseases by genome-wide association (GWAS) studies. Specifically, a single-nucleotide polymorphism (SNP) situated in ZC3HC1 has been shown to predict coronary artery disease.<ref>{{cite journal | vauthors = Jones PD, Kaiser MA, Ghaderi Najafabadi M, McVey DG, Beveridge AJ, Schofield CL, Samani NJ, Webb TR | title = The Coronary Artery Disease-associated Coding Variant in Zinc Finger C3HC-type Containing 1 (ZC3HC1) Affects Cell Cycle Regulation | journal = The Journal of Biological Chemistry | volume = 291 | issue = 31 | pages = 16318–27 | date = July 2016 | pmid = 27226629 | doi = 10.1074/jbc.M116.734020 | pmc=4965579}}</ref><ref>{{cite journal | vauthors = Jones PD, Kaiser MA, Ghaderi Najafabadi M, McVey DG, Beveridge AJ, Schofield CL, Samani NJ, Webb TR | title = The Coronary Artery Disease-associated Coding Variant in Zinc Finger C3HC-type Containing 1 (ZC3HC1) Affects Cell Cycle Regulation | journal = The Journal of Biological Chemistry | volume = 291 | issue = 31 | pages = 16318–27 | date = July 2016 | pmid = 27226629 | pmc = 4965579 | doi = 10.1074/jbc.M116.734020 }}</ref> This prediction appears to be independent of traditional risk factors for cardiovascular disease such as high cholesterol levels, high blood pressure, obesity, smoking and diabetes mellitus, which are primary targets of current treatments for coronary artery disease. Therefore, studying the function of this gene may identify novel pathways contributing to coronary artery disease that result in the development of novel therapeutics.
 
=== Clinical marker ===
At the coronary artery disease-associated locus 7q32.2, only a single SNP (rs11556924) is associated with coronary artery disease risk, with no other variants in strong linkage disequilibrium. The rs11556924 SNP in the ZC3HC1 gene results in an arginine-histidine polymorphism at amino acid residue 363 in NIPA.<ref>{{cite journal | pmid = 16009132 | doi=10.1016/j.cell.2005.04.034 | volume=122 | issue=1 | title=NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry | date=July 2005 | journal=Cell | pages=45–57 | vauthors=Bassermann F, von Klitzing C, Münch S ''et al''}}</ref> Furthermore, rs11556924 has also been associated with altered carotid intima-media thickness in patients with rheumatoid arthritis<ref>{{cite journal | vauthors = López-Mejías R, Genre F, García-Bermúdez M, Corrales A, González-Juanatey C, Llorca J, Miranda-Filloy JA, Rueda-Gotor J, Blanco R, Castañeda S, Martín J, González-Gay MA | title = The ZC3HC1 rs11556924 polymorphism is associated with increased carotid intima-media thickness in patients with rheumatoid arthritis | journal = Arthritis Research & Therapy | volume = 15 | issue = 5 | pages = R152 | date = 2013-01-01 | pmid = 24286297 | doi = 10.1186/ar4335 | pmc=3978706}}</ref> and with altered risk of atrial fibrillation.<ref>{{cite journal | vauthors = Yamase Y, Kato K, Horibe H, Ueyama C, Fujimaki T, Oguri M, Arai M, Watanabe S, Murohara T, Yamada Y | title = Association of genetic variants with atrial fibrillation | journal = Biomedical Reports | volume = 4 | issue = 2 | pages = 178–182 | date = February 2016 | pmid = 26893834 | doi = 10.3892/br.2015.551 | pmc=4734142}}</ref>
 
Additionally, a multi-locus genetic risk score study based on a combination of 27 loci, including the ZC3HC1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on  a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).<ref name="ReferenceA"/>
 
== References ==
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ | title = Shotgun sequencing of the human transcriptome with ORF expressed sequence tags | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 7 | pages = 3491–6 | date = March 2000 | pmid = 10737800 | pmc = 16267 | doi = 10.1073/pnas.97.7.3491 }}
* {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = November 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
* {{cite journal | vauthors = Ouyang T, Bai RY, Bassermann F, von Klitzing C, Klumpen S, Miething C, Morris SW, Peschel C, Duyster J | title = Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA) | journal = The Journal of Biological Chemistry | volume = 278 | issue = 32 | pages = 30028–36 | date = August 2003 | pmid = 12748172 | doi = 10.1074/jbc.M300883200 }}
* {{cite journal | vauthors = Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A | title = From ORFeome to biology: a functional genomics pipeline | journal = Genome Research | volume = 14 | issue = 10B | pages = 2136–44 | date = October 2004 | pmid = 15489336 | pmc = 528930 | doi = 10.1101/gr.2576704 }}
* {{cite journal | vauthors = Bassermann F, von Klitzing C, Münch S, Bai RY, Kawaguchi H, Morris SW, Peschel C, Duyster J | title = NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry | journal = Cell | volume = 122 | issue = 1 | pages = 45–57 | date = July 2005 | pmid = 16009132 | doi = 10.1016/j.cell.2005.04.034 }}
* {{cite journal | vauthors = Ambrogio C, Voena C, Manazza AD, Piva R, Riera L, Barberis L, Costa C, Tarone G, Defilippi P, Hirsch E, Boeri Erba E, Mohammed S, Jensen ON, Palestro G, Inghirami G, Chiarle R | title = p130Cas mediates the transforming properties of the anaplastic lymphoma kinase | journal = Blood | volume = 106 | issue = 12 | pages = 3907–16 | date = December 2005 | pmid = 16105984 | pmc = 1895100 | doi = 10.1182/blood-2005-03-1204 }}
* {{cite journal | vauthors = Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S | title = The LIFEdb database in 2006 | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D415–8 | date = January 2006 | pmid = 16381901 | pmc = 1347501 | doi = 10.1093/nar/gkj139 }}
* {{cite journal | vauthors = Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP | title = A probability-based approach for high-throughput protein phosphorylation analysis and site localization | journal = Nature Biotechnology | volume = 24 | issue = 10 | pages = 1285–92 | date = October 2006 | pmid = 16964243 | doi = 10.1038/nbt1240 }}
* {{cite journal | vauthors = Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M | title = Global, in vivo, and site-specific phosphorylation dynamics in signaling networks | journal = Cell | volume = 127 | issue = 3 | pages = 635–48 | date = November 2006 | pmid = 17081983 | doi = 10.1016/j.cell.2006.09.026 }}
{{refend}}
{{refend}}


{{protein-stub}}
[[Category:Genes mutated in mice]]
{{WikiDoc Sources}}

Latest revision as of 08:41, 9 August 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
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View/Edit Human

Nuclear-interacting partner of ALK (NIPA), also known as zinc finger C3HC-type protein 1 (ZC3HC1), is a protein that in humans is encoded by the ZC3HC1 gene on chromosome 7.[1][2] It is ubiquitously expressed in many tissues and cell types though exclusively expressed in the nuclear subcellular location.[3][4] NIPA is a skp1 cullin F-box (SCF)-type ubiquitin E3 ligase (SCFNIPA) complex protein involved in regulating entry into mitosis.[5] The ZC3HC1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[6]

Structure

Gene

The ZC3HC1 gene resides on chromosome 7 at the band 7q32.2 and includes 14 exons.[2]

Protein

NIPA is a 60-kDa E3 ligase that contains one C3HC-type zinc finger and one F-box-like region.[7][8][8][9] Moreover, a 50-residue region (amino acids 352-402) at its C-terminal serves as the nuclear translocation signal (NLS sequence) while a 96-residue region (amino acids 306-402) is proposed to serve as the phosphotyrosine-binding domain.[5][7] NIPA is one component of the nuclear SCFNIPA complex, and phosphorylation of NIPA at three serine residues, Ser-354, Ser-359 and Ser-395, has been demonstrated to inactivate the complex as a whole.[5]

Function

NIPA is broadly expressed in the human tissues, with the highest expression in heart, skeletal muscle, and testis.[7] It is a human F-box protein that defines an SCF-type ubiquitin E3 ligase, the formation of which is regulated by cell-cycle-dependent phosphorylation of NIPA. Cyclin B1, essential in the entry into mitosis, is targeted by SCFNIPA in interphase. Phosphorylation of NIPA occurs in G2 phase, results in dissociation of NIPA from the SCF core, and has been proven critical for proper G2/M transition.[4] Oscillating ubiquitination of nuclear cyclin B1 driven by the SCFNIPA complex contributes to the timing of mitotic entry.[5][10] NIPA is also reported to delay apoptosis and the localization of NIPA is required for this antiapoptotic function.[7]

Model organisms

Model organisms have been used in the study of ZC3HC1 function. A conditional knockout mouse line, called Zc3hc1tm1a(KOMP)Wtsi[24][25] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[26][27][28]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[22][29] Twenty two tests were carried out on mutant mice and eleven significant abnormalities were observed.[22] Fewer than expected homozygous mutant mice were identified at weaning. Mutants appear to be subfertile, had decreased vertical activity in an open field, decreased lean body mass, decreased rib number and decreased mature B cell number. Males also had a decreased body weight, an abnormal posture and atypical indirect calorimetry data. Females also had an abnormally short snout and atypical haematology parameters .[22]

Clinical relevance

In humans, NIPA has been implicated in cardiovascular diseases by genome-wide association (GWAS) studies. Specifically, a single-nucleotide polymorphism (SNP) situated in ZC3HC1 has been shown to predict coronary artery disease.[30][31] This prediction appears to be independent of traditional risk factors for cardiovascular disease such as high cholesterol levels, high blood pressure, obesity, smoking and diabetes mellitus, which are primary targets of current treatments for coronary artery disease. Therefore, studying the function of this gene may identify novel pathways contributing to coronary artery disease that result in the development of novel therapeutics.

Clinical marker

At the coronary artery disease-associated locus 7q32.2, only a single SNP (rs11556924) is associated with coronary artery disease risk, with no other variants in strong linkage disequilibrium. The rs11556924 SNP in the ZC3HC1 gene results in an arginine-histidine polymorphism at amino acid residue 363 in NIPA.[32] Furthermore, rs11556924 has also been associated with altered carotid intima-media thickness in patients with rheumatoid arthritis[33] and with altered risk of atrial fibrillation.[34]

Additionally, a multi-locus genetic risk score study based on a combination of 27 loci, including the ZC3HC1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[6]

References

  1. ↑ Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z (October 2000). "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells". Genome Research. 10 (10): 1546–60. doi:10.1101/gr.140200. PMC 310934. PMID 11042152.
  2. ↑ 2.0 2.1 "Entrez Gene: ZC3HC1 zinc finger, C3HC-type containing 1".
  3. ↑ "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-11.
  4. ↑ 4.0 4.1 Bassermann F, von Klitzing C, Münch S, Bai RY, Kawaguchi H, Morris SW, Peschel C, Duyster J (July 2005). "NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry". Cell. 122 (1): 45–57. doi:10.1016/j.cell.2005.04.034. PMID 16009132.
  5. ↑ 5.0 5.1 5.2 5.3 Bassermann F, von Klitzing C, Illert AL, Münch S, Morris SW, Pagano M, Peschel C, Duyster J (June 2007). "Multisite phosphorylation of nuclear interaction partner of ALK (NIPA) at G2/M involves cyclin B1/Cdk1". The Journal of Biological Chemistry. 282 (22): 15965–72. doi:10.1074/jbc.M610819200. PMID 17389604.
  6. ↑ 6.0 6.1 Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMC 4608367. PMID 25748612.
  7. ↑ 7.0 7.1 7.2 7.3 Ouyang T, Bai RY, Bassermann F, von Klitzing C, Klumpen S, Miething C, Morris SW, Peschel C, Duyster J (August 2003). "Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA)". The Journal of Biological Chemistry. 278 (32): 30028–36. doi:10.1074/jbc.M300883200. PMID 12748172.
  8. ↑ 8.0 8.1 Kunnas T, Nikkari ST (August 2015). "Association of Zinc Finger, C3HC-Type Containing 1 (ZC3HC1) rs11556924 Genetic Variant With Hypertension in a Finnish Population, the TAMRISK Study". Medicine. 94 (32): e1221. doi:10.1097/MD.0000000000001221. PMC 4616712. PMID 26266351.
  9. ↑ "ZC3HC1 - Nuclear-interacting partner of ALK - Homo sapiens (Human) - ZC3HC1 gene & protein". www.uniprot.org. Retrieved 2016-10-11.
  10. ↑ Bassermann F, Peschel C, Duyster J (November 2005). "Mitotic entry: a matter of oscillating destruction". Cell Cycle. 4 (11): 1515–7. doi:10.4161/cc.4.11.2192. PMID 16258267.
  11. ↑ "Body weight data for Zc3hc1". Wellcome Trust Sanger Institute.
  12. ↑ "Anxiety data for Zc3hc1". Wellcome Trust Sanger Institute.
  13. ↑ "Neurological assessment data for Zc3hc1". Wellcome Trust Sanger Institute.
  14. ↑ "Dysmorphology data for Zc3hc1". Wellcome Trust Sanger Institute.
  15. ↑ "Indirect calorimetry data for Zc3hc1". Wellcome Trust Sanger Institute.
  16. ↑ "DEXA data for Zc3hc1". Wellcome Trust Sanger Institute.
  17. ↑ "Radiography data for Zc3hc1". Wellcome Trust Sanger Institute.
  18. ↑ "Haematology data for Zc3hc1". Wellcome Trust Sanger Institute.
  19. ↑ "Peripheral blood lymphocytes data for Zc3hc1". Wellcome Trust Sanger Institute.
  20. ↑ "Salmonella infection data for Zc3hc1". Wellcome Trust Sanger Institute.
  21. ↑ "Citrobacter infection data for Zc3hc1". Wellcome Trust Sanger Institute.
  22. ↑ 22.0 22.1 22.2 22.3 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  23. ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  24. ↑ "International Knockout Mouse Consortium".
  25. ↑ "Mouse Genome Informatics".
  26. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  27. ↑ Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  28. ↑ Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  29. ↑ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
  30. ↑ Jones PD, Kaiser MA, Ghaderi Najafabadi M, McVey DG, Beveridge AJ, Schofield CL, Samani NJ, Webb TR (July 2016). "The Coronary Artery Disease-associated Coding Variant in Zinc Finger C3HC-type Containing 1 (ZC3HC1) Affects Cell Cycle Regulation". The Journal of Biological Chemistry. 291 (31): 16318–27. doi:10.1074/jbc.M116.734020. PMC 4965579. PMID 27226629.
  31. ↑ Jones PD, Kaiser MA, Ghaderi Najafabadi M, McVey DG, Beveridge AJ, Schofield CL, Samani NJ, Webb TR (July 2016). "The Coronary Artery Disease-associated Coding Variant in Zinc Finger C3HC-type Containing 1 (ZC3HC1) Affects Cell Cycle Regulation". The Journal of Biological Chemistry. 291 (31): 16318–27. doi:10.1074/jbc.M116.734020. PMC 4965579. PMID 27226629.
  32. ↑ Bassermann F, von Klitzing C, Münch S, et al. (July 2005). "NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry". Cell. 122 (1): 45–57. doi:10.1016/j.cell.2005.04.034. PMID 16009132.
  33. ↑ López-Mejías R, Genre F, García-Bermúdez M, Corrales A, González-Juanatey C, Llorca J, Miranda-Filloy JA, Rueda-Gotor J, Blanco R, Castañeda S, Martín J, González-Gay MA (2013-01-01). "The ZC3HC1 rs11556924 polymorphism is associated with increased carotid intima-media thickness in patients with rheumatoid arthritis". Arthritis Research & Therapy. 15 (5): R152. doi:10.1186/ar4335. PMC 3978706. PMID 24286297.
  34. ↑ Yamase Y, Kato K, Horibe H, Ueyama C, Fujimaki T, Oguri M, Arai M, Watanabe S, Murohara T, Yamada Y (February 2016). "Association of genetic variants with atrial fibrillation". Biomedical Reports. 4 (2): 178–182. doi:10.3892/br.2015.551. PMC 4734142. PMID 26893834.

Further reading

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