Reviewed, UniProtKB/Swiss-Prot Q8N726 (CD2A2_HUMAN)

Names and origin

Protein names

Recommended name:
    Cyclin-dependent kinase inhibitor 2A, isoform 4
Alternative name(s):
    p14ARF
    p19ARF

Gene names

Name:	CDKN2A
Synonyms:	CDKN2, MLM

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	173 AA.
Sequence status	Complete.
Protein existence	Evidence 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	Nucleus › nucleolus By similarity.

Ontologies

Keywords
Biological process	Apoptosis Cell cycle Transcription Transcription regulation rRNA processing
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Tumor suppressor
Ligand	DNA-binding
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	DNA 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 component	nucleolus Ref.19 Inferred from direct assay. Source: UniProtKB nucleoplasm Ref.19 Inferred from direct assay. Source: UniProtKB
Molecular function	protein 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...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DAXX	Q9UER7	3	EBI-625922,EBI-77321
EBNA-LP	Q8AZK7	1	EBI-625922,EBI-1185167	From a different organism.
HUWE1	Q7Z6Z7	2	EBI-625922,EBI-625934
MDM2	Q00987	3	EBI-625922,EBI-389668
PPP1CB	P62140	1	EBI-625922,EBI-352350
PPP1CC	P36873-1	1	EBI-625922,EBI-356289

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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 173	173	Cyclin-dependent kinase inhibitor 2A, isoform 4		PRO_0000144180
Natural variations
	Natural variant	58	1	P → S: dbSNP rs3731190. Ref.3		VAR_029287
	Natural variant	147	1	G → R: dbSNP rs4987127.		VAR_053033
	Natural variant	154	1	P → L: dbSNP rs34886500.		VAR_053034
	Natural variant	157	1	G → D: dbSNP rs35741010.		VAR_053035
Experimental info
	Sequence conflict	38	1	G → R in AAB01737. Ref.2
	Sequence conflict	69 – 71	3	PRL → SWF in AAP35666. Ref.6
	Sequence conflict	135	1	P → L in AAB01737. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 4 (p14ARF) (p19ARF) (ARF) [UniParc]. Last modified October 1, 2002. Version 1. Checksum: 8B3106601B367EDD	FASTA	173	18,006
	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
	Isoform 1 (p16INK4a). See P42771.	FASTA	–	–
	Isoform 2. See P42771.	FASTA	–	–
	Isoform 3 (p12). See P42771.	FASTA	–	–

References

	« Hide 'large scale' referencesShow '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. , 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

NIEHS-SNPs

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.
IPI	IPI00478390.
PIR	I39004.
RefSeq	NP_000068.1. NP_478102.1.
UniGene	Hs.512599
3D structure databases
SMR	Q8N726. Positions 39-71.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-24171N.
IntAct	Q8N726. 9 interactions.
STRING	Q8N726.
Proteomic databases
PeptideAtlas	Q8N726.
PRIDE	Q8N726.
Genome annotation databases
Ensembl	ENST00000361570; ENSP00000355153; ENSG00000147889; Homo sapiens. [Genome view]
GeneID	1029.
KEGG	hsa:1029.
UCSC	uc003zpl.1. human.
Organism-specific databases
CTD	1029.
GeneCards	GC09M021957.
H-InvDB	HIX0018963.
HGNC	HGNC:1787. CDKN2A.
HPA	CAB000093. CAB000445. CAB018232.
MIM	600160. gene.
Orphanet	618. Melanoma, familial. 51013. Melanoma-pancreatic cancer, syndrome. 1333. Pancreatic carcinoma, familial.
PharmGKB	PA106.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	Q8N726.
InParanoid	Q8N726.
OrthoDB	EOG9C2KXB.
Enzyme and pathway databases
Pathway_Interaction_DB	pi3kciaktpathway. 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
ArrayExpress	Q8N726.
Bgee	Q8N726.
CleanEx	HS_CDKN2A.
Genevestigator	Q8N726.
GermOnline	ENSG00000147889. Homo sapiens.
Family and domain databases
InterPro	IPR010868. P19Arf_N. [Graphical view]
PANTHER	PTHR21414. P19Arf_N. 1 hit.
Pfam	PF07392. P19Arf_N. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	4323.
SOURCE	Search...

Entry information

Entry name

CD2A2_HUMAN

Accession

Primary (citable) accession number: Q8N726
Secondary accession number(s): Q13195 , 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 status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.