ExPASy logo ExPASy Home page Site Map Search ExPASy Contact us Swiss-Prot
Notice: This page will be replaced with www.uniprot.org. Please send us your feedback!
Search for

UniProtKB/Swiss-Prot entry Q8N726


[Entry info] [Name and origin] [References] [Comments] [Cross-references] [Keywords] [Features] [Sequence] [Tools]

Note: most headings are clickable, even if they don't appear as links. They link to the user manual or other documents.
Entry information
Entry name CD2A2_HUMAN
Primary accession number Q8N726
Secondary accession numbers Q13195 Q13399 Q16360 Q7KZR9
Integrated into Swiss-Prot on October 11, 2005
Sequence was last modified on October 1, 2002 (Sequence version 1)
Annotations were last modified on    November 25, 2008 (Entry version 52)
Name and origin of the protein
Protein name Cyclin-dependent kinase inhibitor 2A, isoform 4
Synonyms p14ARF
p19ARF
Gene name
Name: CDKN2A
Synonyms: CDKN2, MLM
From
Homo sapiens (Human) [TaxID: 9606] 
Taxonomy Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.
Protein existence 1: Evidence at protein level;
References
[1]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=7606716 [NCBI, ExPASy, EBI, Israel, Japan]
Stone S., Jiang P., Dayananth P., Tavtigian S.V., Katcher H., Parry D., Peters G., Kamb A.;
"Complex structure and regulation of the P16 (MTS1) locus.";
Cancer Res. 55:2988-2994(1995).
[2]
NUCLEOTIDE SEQUENCE [MRNA].
Linnenbach A.J.;
"mRNA isoform with alternate first exon-encoded sequences at the cyclin-dependent kinase inhibitor 2 (p16INK4/MTS1) locus and mapping analysis of the region by using long-PCR.";
Submitted (OCT-1995) to the EMBL/GenBank/DDBJ databases.
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Rieder M.J., Livingston R.J., Daniels M.R., Montoya M.A., Chung M.-W., Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A.;
"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu).";
Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
DOI=10.1038/nature02465; PubMed=15164053 [NCBI, ExPASy, EBI, Israel, Japan]
Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., Dunham I.;
"DNA sequence and analysis of human chromosome 9.";
Nature 429:369-374(2004).
[5]
NUCLEOTIDE SEQUENCE [MRNA] OF 33-173.
TISSUE=Hematopoietic;
PubMed=7624129 [NCBI, ExPASy, EBI, Israel, Japan]
Duro D., Bernard O., Della Valle V., Berger R., Larsen C.J.;
"A new type of p16INK4/MTS1 gene transcript expressed in B-cell malignancies.";
Oncogene 11:21-29(1995).
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 42-173.
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.;
"Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
[7]
FUNCTION, AND INTERACTION WITH MDM2.
DOI=10.1093/emboj/17.17.5001; PubMed=9724636 [NCBI, ExPASy, EBI, Israel, Japan]
Stott F.J., Bates S., James M.C., McConnell B.B., Starborg M., Brookes S., Palmero I., Ryan K., Hara E., Vousden K.H., Peters G.;
"The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2.";
EMBO J. 17:5001-5014(1998).
[8]
FUNCTION, AND INTERACTION WITH TOP1.
DOI=10.1038/sj.onc.1204170; PubMed=11314011 [NCBI, ExPASy, EBI, Israel, Japan]
Karayan L., Riou J.-F., Seite P., Migeon J., Cantereau A., Larsen C.-J.;
"Human ARF protein interacts with topoisomerase I and stimulates its activity.";
Oncogene 20:836-848(2001).
[9]
FUNCTION, AND INTERACTION WITH E2F1.
DOI=10.1038/sj.onc.1204220; PubMed=11314038 [NCBI, ExPASy, EBI, Israel, Japan]
Eymin B., Karayan L., Seite P., Brambilla C., Brambilla E., Larsen C.-J., Gazzeri S.;
"Human ARF binds E2F1 and inhibits its transcriptional activity.";
Oncogene 20:1033-1041(2001).
[10]
INTERACTION WITH CDKN2AIP.
DOI=10.1074/jbc.M204177200; PubMed=12154087 [NCBI, ExPASy, EBI, Israel, Japan]
Hasan M.K., Yaguchi T., Sugihara T., Kumar P.K.R., Taira K., Reddel R.R., Kaul S.C., Wadhwa R.;
"CARF is a novel protein that cooperates with mouse p19ARF (human p14ARF) in activating p53.";
J. Biol. Chem. 277:37765-37770(2002).
[11]
INTERACTION WITH CDKN2AIP.
DOI=10.1016/S0531-5565(02)00180-8; PubMed=12581788 [NCBI, ExPASy, EBI, Israel, Japan]
Wadhwa R., Sugihara T., Hasan M.K., Duncan E.L., Taira K., Kaul S.C.;
"A novel putative collaborator of p19ARF.";
Exp. Gerontol. 38:245-252(2003).
[12]
INTERACTION WITH E4F1.
DOI=10.1074/jbc.M210978200; PubMed=12446718 [NCBI, ExPASy, EBI, Israel, Japan]
Rizos H., Diefenbach E., Badhwar P., Woodruff S., Becker T.M., Rooney R.J., Kefford R.F.;
"Association of p14ARF with the p120E4F transcriptional repressor enhances cell cycle inhibition.";
J. Biol. Chem. 278:4981-4989(2003).
[13]
FUNCTION, AND INTERACTION WITH NPM1.
DOI=10.1016/S1097-2765(03)00431-3; PubMed=14636574 [NCBI, ExPASy, EBI, Israel, Japan]
Itahana K., Bhat K.P., Jin A., Itahana Y., Hawke D., Kobayashi R., Zhang Y.;
"Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation.";
Mol. Cell 12:1151-1164(2003).
[14]
FUNCTION.
DOI=10.1038/sj.onc.1206303; PubMed=12660818 [NCBI, ExPASy, EBI, Israel, Japan]
Eymin B., Leduc C., Coll J.-L., Brambilla E., Gazzeri S.;
"p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice.";
Oncogene 22:1822-1835(2003).
[15]
FUNCTION, AND INTERACTION WITH TOP1.
DOI=10.1038/sj.onc.1207968; PubMed=15361825 [NCBI, ExPASy, EBI, Israel, Japan]
Ayrault O., Andrique L., Larsen C.-J., Seite P.;
"Human Arf tumor suppressor specifically interacts with chromatin containing the promoter of rRNA genes.";
Oncogene 23:8097-8104(2004).
[16]
FUNCTION, AND INTERACTION WITH BCL6.
DOI=10.1016/j.bbrc.2004.11.016; PubMed=15567177 [NCBI, ExPASy, EBI, Israel, Japan]
Suzuki H., Kurita M., Mizumoto K., Moriyama M., Aiso S., Nishimoto I., Matsuoka M.;
"The ARF tumor suppressor inhibits BCL6-mediated transcriptional repression.";
Biochem. Biophys. Res. Commun. 326:242-248(2005).
[17]
FUNCTION, AND INTERACTION WITH HUWE1.
DOI=10.1016/j.cell.2005.03.037; PubMed=15989956 [NCBI, ExPASy, EBI, Israel, Japan]
Chen D., Kon N., Li M., Zhang W., Qin J., Gu W.;
"ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor.";
Cell 121:1071-1083(2005).
[18]
FUNCTION, AND INTERACTION WITH UBE2I.
PubMed=15876874 [NCBI, ExPASy, EBI, Israel, Japan]
Rizos H., Woodruff S., Kefford R.F.;
"p14ARF interacts with the SUMO-conjugating enzyme Ubc9 and promotes the sumoylation of its binding partners.";
Cell Cycle 4:597-603(2005).
[19]
INTERACTION WITH TBRG1.
DOI=10.1074/jbc.M609612200; PubMed=17110379 [NCBI, ExPASy, EBI, Israel, Japan]
Tompkins V.S., Hagen J., Frazier A.A., Lushnikova T., Fitzgerald M.P., di Tommaso A.D., Ladeveze V., Domann F.E., Eischen C.M., Quelle D.E.;
"A novel nuclear interactor of ARF and MDM2 (NIAM) that maintains chromosomal stability.";
J. Biol. Chem. 282:1322-1333(2007).
Comments
  • FUNCTION: Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development.
  • SUBUNIT: Does not interact with cyclins, CDC2, CDK2, CDK4, CDK5 or CDK6. Binds to BCL6, E2F1, HUWE1, MDM2, MYC, NPM1/B23, TOP1/TOPOI and UBE2I/UBC9. Interacts with TBRG1. Interacts with CDKN2AIP and E4F1.
  • INTERACTION:
    Q8AZK7:EBNA-LP (xeno); NbExp=1; IntAct=EBI-625922, EBI-1185167;
    Q7Z6Z7:HUWE1; NbExp=2; IntAct=EBI-625922, EBI-625934;
    Q00987:MDM2; NbExp=2; IntAct=EBI-625922, EBI-389668;
    P62140:PPP1CB; NbExp=1; IntAct=EBI-625922, EBI-352350;
    P36873-1:PPP1CC; NbExp=1; IntAct=EBI-625922, EBI-356289;
  • SUBCELLULAR LOCATION: Nucleus, nucleolus (By similarity).
  • ALTERNATIVE PRODUCTS: 4 named isoforms [FASTA] produced by alternative splicing. Isoform 1 and isoform 4 arise due to the use of two alternative first exons joined to a common exon 2 at the same acceptor site but in different reading frames, resulting in two completely different isoforms.
    Name4
    Synonymsp14ARF, p19ARF, ARF
    Isoform IDQ8N726-1
    This is the isoform sequence displayed in this entry.
    Name1
    Synonymsp16INK4a
    Isoform IDP42771-1
    This isoform is stored in UniProtKB/Swiss-Prot entry P42771.
    Name2
    Isoform IDP42771-2
    This isoform is stored in UniProtKB/Swiss-Prot entry P42771.
    Name3
    Synonymsp12
    Isoform IDP42771-3
    This isoform is stored in UniProtKB/Swiss-Prot entry P42771.
Copyright
Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.
Cross-references
Sequence databases
EMBL
S78535; AAC60649.1; ALT_INIT; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
U38945; AAB01737.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AF527803; AAM77919.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AL449423; CAH70601.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
U26727; AAA82236.1; ALT_INIT; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
BT007020; AAP35666.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
PIR I39004; I39004.
RefSeq NP_478102.1; -.
UniGene Hs.512599
3D structure databases
HSSP Q64364; 1HN3. [HSSP ENTRY / PDB]
ModBase Q8N726.
Protein-protein interaction databases
DIP DIP:24171N; -.
IntAct Q8N726; -.
Polymorphism databases
NIEHS-SNPs CDKN2A.
Organism-specific databases
H-InvDB HIX0018963; -.
HGNC HGNC:1787; CDKN2A.
GenAtlas CDKN2A.
HPA CAB000445; -.
CAB018232; -.
MIM 600160; gene. [NCBI / EBI]
Orphanet 618; Melanoma, familial.
51013; Melanoma-pancreatic cancer, syndrome.
PharmGKB PA106; -.
GeneCards Q8N726.
Gene expression databases
ArrayExpress Q8N726; -.
CleanEx HS_CDKN2A; -.
GermOnline ENSG00000147889; Homo sapiens.
Ontologies
GO
GO:0005730; Cellular component: nucleolus (inferred from direct assay from UniProtKB).
GO:0005654; Cellular component: nucleoplasm (inferred from direct assay from UniProtKB).
GO:0003677; Molecular function: DNA binding (inferred from electronic annotation from UniProtKB-KW).
GO:0005515; Molecular function: protein binding (inferred from physical interaction from IntAct).
GO:0055105; Molecular function: ubiquitin-protein ligase inhibitor activity (inferred from sequence or structural similarity from UniProtKB).
GO:0008637; Biological process: apoptotic mitochondrial changes (inferred from mutant phenotype from UniProtKB).
GO:0006919; Biological process: caspase activation (inferred from mutant phenotype from UniProtKB).
GO:0007050; Biological process: cell cycle arrest (inferred from mutant phenotype from UniProtKB).
GO:0006309; Biological process: DNA fragmentation during apoptosis (inferred from mutant phenotype from UniProtKB).
GO:0006917; Biological process: induction of apoptosis (inferred from mutant phenotype from UniProtKB).
GO:0030889; Biological process: negative regulation of B cell proliferation (inferred from sequence or structural similarity from UniProtKB).
GO:0045786; Biological process: negative regulation of cell cycle (inferred from electronic annotation from UniProtKB-KW).
GO:0033088; Biological process: negative regulation of immature T cell proliferation in the thymus (inferred from sequence or structural similarity from UniProtKB).
GO:0006469; Biological process: negative regulation of protein kinase activity (inferred from mutant phenotype from UniProtKB).
GO:0051444; Biological process: negative regulation of ubiquitin-protein ligase activity (inferred from sequence or structural similarity from UniProtKB).
GO:0010389; Biological process: regulation of G2/M transition of mitotic cell cycle (inferred from mutant phenotype from UniProtKB).
GO:0031647; Biological process: regulation of protein stability (inferred from sequence or structural similarity from UniProtKB).
GO:0006355; Biological process: regulation of transcription, DNA-dependent (inferred from electronic annotation from UniProtKB-KW).
GO:0006364; Biological process: rRNA processing (inferred from electronic annotation from UniProtKB-KW).
GO:0010149; Biological process: senescence (inferred from mutant phenotype from UniProtKB).
GO:0048103; Biological process: somatic stem cell division (inferred from sequence or structural similarity from UniProtKB).
QuickGo view.
Family and domain databases
InterPro IPR010868; P19Arf_N.
Graphical view of domain structure.
PANTHER PTHR21414; P19Arf_N; 1.
Pfam PF07392; P19Arf_N; 1.
Pfam graphical view of domain structure.
ProtoNet Q8N726.
Proteomic databases
PeptideAtlas Q8N726; -.
Genome annotation databases
Ensembl ENSG00000147889; Homo sapiens. [Contig view]
GeneID 1029; -.
Phylogenomic databases
HOGENOM Q8N726; -.
HOVERGEN Q8N726; -.
Other
NextBio 4323; -.
SOURCE CDKN2A; Homo sapiens.
UniRef View cluster of proteins with at least 50% / 90% / 100% identity.
Keywords
Alternative splicing; Anti-oncogene; Apoptosis; Cell cycle; DNA-binding; Nucleus; Polymorphism; rRNA processing; Transcription; Transcription regulation.
Features
SEVIEWER logo Feature table viewer
KeyFrom   To Length Description FTId
CHAIN   1   173  173     Cyclin-dependent kinase inhibitor 2A, isoform 4. PRO_0000144180
VARIANT   58    58  1     P -> S (in dbSNP:rs3731190 [NCBI]). VAR_029287 
CONFLICT   38    38        G -> R (in Ref. 2; AAB01737). 
CONFLICT   69    71        PRL -> SWF (in Ref. 6). 
CONFLICT   135   135        P -> L (in Ref. 2; AAB01737). 
Sequence information
Length: 173 AA [This is the length of the unprocessed precursor] Molecular weight: 18006 Da [This is the MW of the unprocessed precursor] CRC64: 8B3106601B367EDD [This is a checksum on the sequence]
        10         20         30         40         50         60 
MGRGRCVGPS LQLRGQEWRC SPLVPKGGAA AAELGPGGGE NMVRRFLVTL RIRRACGPPR 

        70         80         90        100        110        120 
VRVFVVHIPR LTGEWAAPGA PAAVALVLML LRSQRLGQQP LPRRPGHDDG QRPSGGAAAA 

       130        140        150        160        170 
PRRGAQLRRP RHSHPTRARR CPGGLPGHAG GAAPGRGAAG RARCLGPSAR GPG 

Q8N726 in FASTA format

View entry in original UniProtKB/Swiss-Prot format
View entry in raw text format (no links)
Report form for errors/updates in this UniProtKB/Swiss-Prot entry

BLAST logo BLAST submission on ExPASy/SIB
or at NCBI (USA)
Tools Sequence analysis tools: ProtParam, ProtScale, Compute pI/Mw, PeptideMass, PeptideCutter, Dotlet (Java)
PROSITE logo ScanProsite, MotifScan SWISS-MODEL Submit a homology modeling request to SWISS-MODEL
NPSA logo NPSA Sequence analysis tools

ExPASy logo ExPASy Home page Site Map Search ExPASy Contact us Swiss-Prot
 Hosted by ch flag SIB Switzerland Mirror sites: Australia  Brazil  Canada  China  Korea
Notice: This page will be replaced with www.uniprot.org. Please send us your feedback!