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Reviewed, UniProtKB/Swiss-Prot Q8N726 (CD2A2_HUMAN)

Last modified February 9, 2010. Version 70. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Cyclin-dependent kinase inhibitor 2A, isoform 4
Alternative name(s):
    p14ARF
    p19ARF
Gene names
Name: CDKN2A
Synonyms: CDKN2, MLM
OrganismHomo sapiens (Human) [Complete proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length173 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level.

General annotation (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. Ref.7 Ref.8 Ref.9 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 UniProtKB Q64364

Subunit structure

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. Ref.7 Ref.8 Ref.9 Ref.13 Ref.15 Ref.16 Ref.17 Ref.18 Ref.10 Ref.11 Ref.12 Ref.19 UniProtKB Q64364

Subcellular location

Nucleusnucleolus By similarity.

Ontologies

Keywords
   Biological processApoptosis
Cell cycle
Transcription
Transcription regulation
rRNA processing
   Cellular componentNucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseTumor suppressor
   LigandDNA-binding
   Technical termComplete proteome
Gene Ontology (GO)
   Biological processDNA fragmentation involved in apoptosis

Inferred from mutant phenotype. Source: UniProtKB

activation of caspase activity

Inferred from mutant phenotype. Source: UniProtKB

apoptotic mitochondrial changes

Inferred from mutant phenotype. Source: UniProtKB

cell cycle arrest

Inferred from mutant phenotype. Source: UniProtKB

induction of apoptosis

Inferred from mutant phenotype. Source: UniProtKB

negative regulation of B cell proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of immature T cell proliferation in the thymus

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of ubiquitin-protein ligase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein stabilization

Inferred from direct assay. Source: UniProtKB

rRNA processing

Inferred from electronic annotation. Source: UniProtKB-KW

regulation of G2/M transition of mitotic cell cycle

Inferred from mutant phenotype. Source: UniProtKB

regulation of protein export from nucleus

Inferred from mutant phenotype. Source: UniProtKB

regulation of protein stability

Inferred from sequence or structural similarity. Source: UniProtKB

senescence

Inferred from mutant phenotype. Source: UniProtKB

somatic stem cell division

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular componentnucleolus Ref.19

Inferred from direct assay. Source: UniProtKB

nucleoplasm Ref.19

Inferred from direct assay. Source: UniProtKB

   Molecular functionprotein binding Ref.11 Ref.17 Ref.19

Inferred from physical interaction. Source: IntAct

ubiquitin-protein ligase inhibitor activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Note: 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.
Isoform 4 Ref.1 (identifier: Q8N726-1)

Also known as: p14ARF; p19ARF; ARF;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 1 (identifier: P42771-1)

Also known as: p16INK4a;

The sequence of this isoform can be found in the external entry P42771-1.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.
Isoform 2 (identifier: P42771-2)

The sequence of this isoform can be found in the external entry P42771-2.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.
Isoform 3 (identifier: P42771-3)

Also known as: p12;

The sequence of this isoform can be found in the external entry P42771-3.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 173173Cyclin-dependent kinase inhibitor 2A, isoform 4
PRO_0000144180

Natural variations

Natural variant581P → S: dbSNP rs3731190. Ref.3
VAR_029287
Natural variant1471G → R: dbSNP rs4987127.
VAR_053033
Natural variant1541P → L: dbSNP rs34886500.
VAR_053034
Natural variant1571G → D: dbSNP rs35741010.
VAR_053035

Experimental info

Sequence conflict381G → R in AAB01737. Ref.2
Sequence conflict69 – 713PRL → SWF in AAP35666. Ref.6
Sequence conflict1351P → L in AAB01737. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform 4 (p14ARF) (p19ARF) (ARF) [UniParc].

Last modified October 1, 2002. Version 1.
Checksum: 8B3106601B367EDD

FASTA17318,006
        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 

« Hide

Isoform 1 (p16INK4a).

See P42771.

FASTA
Isoform 2.

See P42771.

FASTA
Isoform 3 (p12).

See P42771.

FASTA

References

« Hide 'large scale' references
[1]"Complex structure and regulation of the P16 (MTS1) locus."
Stone S., Jiang P., Dayananth P., Tavtigian S.V., Katcher H., Parry D., Peters G., Kamb A.
Cancer Res. 55:2988-2994(1995) [PubMed: 7606716] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"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."
Linnenbach A.J.
Submitted (OCT-1995) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]NIEHS SNPs program
Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT SER-58.
[4]"DNA sequence and analysis of human chromosome 9."
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. expand/collapse author list , 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.
Nature 429:369-374(2004) [PubMed: 15164053] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"A new type of p16INK4/MTS1 gene transcript expressed in B-cell malignancies."
Duro D., Bernard O., Della Valle V., Berger R., Larsen C.J.
Oncogene 11:21-29(1995) [PubMed: 7624129] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 33-173.
Tissue: Hematopoietic.
[6]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
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.
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 42-173.
[7]"The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2."
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.
EMBO J. 17:5001-5014(1998) [PubMed: 9724636] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MDM2.
[8]"Human ARF protein interacts with topoisomerase I and stimulates its activity."
Karayan L., Riou J.-F., Seite P., Migeon J., Cantereau A., Larsen C.-J.
Oncogene 20:836-848(2001) [PubMed: 11314011] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TOP1.
[9]"Human ARF binds E2F1 and inhibits its transcriptional activity."
Eymin B., Karayan L., Seite P., Brambilla C., Brambilla E., Larsen C.-J., Gazzeri S.
Oncogene 20:1033-1041(2001) [PubMed: 11314038] [Abstract]
Cited for: FUNCTION, INTERACTION WITH E2F1.
[10]"CARF is a novel protein that cooperates with mouse p19ARF (human p14ARF) in activating p53."
Hasan M.K., Yaguchi T., Sugihara T., Kumar P.K.R., Taira K., Reddel R.R., Kaul S.C., Wadhwa R.
J. Biol. Chem. 277:37765-37770(2002) [PubMed: 12154087] [Abstract]
Cited for: INTERACTION WITH CDKN2AIP.
[11]"A novel putative collaborator of p19ARF."
Wadhwa R., Sugihara T., Hasan M.K., Duncan E.L., Taira K., Kaul S.C.
Exp. Gerontol. 38:245-252(2003) [PubMed: 12581788] [Abstract]
Cited for: INTERACTION WITH CDKN2AIP.
[12]"Association of p14ARF with the p120E4F transcriptional repressor enhances cell cycle inhibition."
Rizos H., Diefenbach E., Badhwar P., Woodruff S., Becker T.M., Rooney R.J., Kefford R.F.
J. Biol. Chem. 278:4981-4989(2003) [PubMed: 12446718] [Abstract]
Cited for: INTERACTION WITH E4F1.
[13]"Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation."
Itahana K., Bhat K.P., Jin A., Itahana Y., Hawke D., Kobayashi R., Zhang Y.
Mol. Cell 12:1151-1164(2003) [PubMed: 14636574] [Abstract]
Cited for: FUNCTION, INTERACTION WITH NPM1.
[14]"p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice."
Eymin B., Leduc C., Coll J.-L., Brambilla E., Gazzeri S.
Oncogene 22:1822-1835(2003) [PubMed: 12660818] [Abstract]
Cited for: FUNCTION.
[15]"Human Arf tumor suppressor specifically interacts with chromatin containing the promoter of rRNA genes."
Ayrault O., Andrique L., Larsen C.-J., Seite P.
Oncogene 23:8097-8104(2004) [PubMed: 15361825] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TOP1.
[16]"The ARF tumor suppressor inhibits BCL6-mediated transcriptional repression."
Suzuki H., Kurita M., Mizumoto K., Moriyama M., Aiso S., Nishimoto I., Matsuoka M.
Biochem. Biophys. Res. Commun. 326:242-248(2005) [PubMed: 15567177] [Abstract]
Cited for: FUNCTION, INTERACTION WITH BCL6.
[17]"ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor."
Chen D., Kon N., Li M., Zhang W., Qin J., Gu W.
Cell 121:1071-1083(2005) [PubMed: 15989956] [Abstract]
Cited for: FUNCTION, INTERACTION WITH HUWE1.
[18]"p14ARF interacts with the SUMO-conjugating enzyme Ubc9 and promotes the sumoylation of its binding partners."
Rizos H., Woodruff S., Kefford R.F.
Cell Cycle 4:597-603(2005) [PubMed: 15876874] [Abstract]
Cited for: FUNCTION, INTERACTION WITH UBE2I.
[19]"A novel nuclear interactor of ARF and MDM2 (NIAM) that maintains chromosomal stability."
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.
J. Biol. Chem. 282:1322-1333(2007) [PubMed: 17110379] [Abstract]
Cited for: INTERACTION WITH TBRG1.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
S78535 mRNA. Translation: AAC60649.1. Different initiation.
U38945 mRNA. Translation: AAB01737.1.
AF527803 Genomic DNA. Translation: AAM77919.1.
AL449423 Genomic DNA. Translation: CAH70601.1.
U26727 mRNA. Translation: AAA82236.1. Different initiation.
BT007020 mRNA. Translation: AAP35666.1.
IPIIPI00478390.
PIRI39004.
RefSeqNP_000068.1.
NP_478102.1.
UniGeneHs.512599

3D structure databases

SMRQ8N726. Positions 39-71.
ModBaseSearch...

Protein-protein interaction databases

DIPDIP-24171N.
IntActQ8N726. 9 interactions.
STRINGQ8N726.

Proteomic databases

PeptideAtlasQ8N726.
PRIDEQ8N726.

Genome annotation databases

EnsemblENST00000361570; ENSP00000355153; ENSG00000147889; Homo sapiens. [Genome view]
GeneID1029.
KEGGhsa:1029.
UCSCuc003zpl.1. human.

Organism-specific databases

CTD1029.
GeneCardsGC09M021957.
H-InvDBHIX0018963.
HGNCHGNC:1787. CDKN2A.
HPACAB000093.
CAB000445.
CAB018232.
MIM600160. gene.
Orphanet618. Melanoma, familial.
51013. Melanoma-pancreatic cancer, syndrome.
1333. Pancreatic carcinoma, familial.
PharmGKBPA106.
GenAtlasSearch...

Phylogenomic databases

HOVERGENQ8N726.
InParanoidQ8N726.
OrthoDBEOG9C2KXB.

Enzyme and pathway databases

Pathway_Interaction_DBpi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
foxm1pathway. FOXM1 transcription factor network.
hif1apathway. Hypoxic and oxygen homeostasis regulation of HIF-1-alpha.

Gene expression databases

ArrayExpressQ8N726.
BgeeQ8N726.
CleanExHS_CDKN2A.
GenevestigatorQ8N726.
GermOnlineENSG00000147889. Homo sapiens.

Family and domain databases

InterProIPR010868. P19Arf_N.
[Graphical view]
PANTHERPTHR21414. P19Arf_N. 1 hit.
PfamPF07392. P19Arf_N. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio4323.
SOURCESearch...

Entry information

Entry nameCD2A2_HUMAN
AccessionPrimary (citable) accession number: Q8N726
Secondary accession number(s): Q13195 expand/collapse secondary AC list , Q13399, Q16360, Q7KZR9
Entry history
Integrated into UniProtKB/Swiss-Prot: October 11, 2005
Last sequence update: October 1, 2002
Last modified: February 9, 2010
This is version 70 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

Human chromosome 9

Human chromosome 9: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents