Cyclin-dependent kinase inhibitor 2A, isoform 3

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Q64364 (CD2A2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified May 1, 2013. Version 103. History...

Clusters with 100%, 90%, 50% identity |

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Names·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents Customize order

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase inhibitor 2A, isoform 3

Alternative name(s):
p19ARF

Gene names

Name:

Cdkn2a

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	169 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 COMMD1 and promotes its 'Lys63'-linked polyubiquitination By similarity. 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. Isoform 4 may be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP. Ref.1 Ref.6 Ref.7 Ref.8 Ref.9 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 UniProtKB Q8N726
Subunit structure	Does not interact with cyclins, CDK1, CDK2, CDK4, CDK5 or CDK6. Interacts with COMMD1 By similarity. Binds to BCL6, E2F1, HUWE1, MDM2, MYC, NPM1/B23, TOP1/TOPOI and UBE2I/UBC9. Interacts with TBRG1. Interacts with CDKN2AIP and E4F1. Isoform 4 interacts with C1QBP. Ref.8 Ref.11 Ref.13 Ref.14 Ref.18 Ref.19
Subcellular location	Nucleus › nucleolus. Nucleus › nucleoplasm By similarity Ref.1 Ref.9 Ref.14 Ref.15 Ref.16. Isoform 4: Mitochondrion Ref.1 Ref.9 Ref.14 Ref.15 Ref.16.
Developmental stage	Not detected in 12-week virgin mammary glands. Expression increases (at protein level) six-fold during pregnancy and remains at this level during lactation. During involution, a slight increase is observed at days 2 and 8 followed by a sharp decline at day 15. Ref.12
Induction	By progesterone. Induced by activated Ras, and this requires DMTF1. Repressed by non-classical inhibitors of NF-kappa-B signaling such as doxorubicin, daunorubicin and UVC, and by the NF-kappa-B p65 subunit (RELA). Ref.10 Ref.12 Ref.15 Ref.20
Post-translational modification	Ubiquitinated in normal cells by TRIP12 via the ubiquitin fusion degradation (UFD) pathway, a process that mediates ubiquitination at the N-terminus, regardeless of the absence of lysine residues. Ubiquitination leads to its degradation. In cancer cells, however, TRIP12 is located in a different cell compartment, preventing ubiquitination and degradation By similarity.
Disruption phenotype	Mice lacking isoform p19ARF of Cdkn2a display delayed mammary gland involution. Ref.12

Ontologies

Keywords
Biological process	Apoptosis Cell cycle Transcription Transcription regulation Ubl conjugation pathway rRNA processing
Cellular component	Mitochondrion Nucleus
Coding sequence diversity	Alternative splicing
Disease	Tumor suppressor
Ligand	DNA-binding
PTM	Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cell aging Inferred from direct assay PubMed 11748239. Source: MGI cell cycle arrest Inferred from direct assay PubMed 7651726. Source: MGI epidermis development Inferred from mutant phenotype PubMed 11551927. Source: MGI negative regulation of B cell proliferation Inferred from mutant phenotype PubMed 15964995. Source: HGNC negative regulation of cell growth Inferred from mutant phenotype Ref.11. Source: BHF-UCL negative regulation of cyclin-dependent protein serine/threonine kinase activity Inferred from direct assay PubMed 12130539. Source: MGI negative regulation of immature T cell proliferation in thymus Inferred from mutant phenotype PubMed 15964995. Source: HGNC negative regulation of mammary gland epithelial cell proliferation Inferred from mutant phenotype Ref.12. Source: MGI negative regulation of ubiquitin-protein ligase activity Inferred from direct assay PubMed 9878046. Source: BHF-UCL positive regulation of DNA damage response, signal transduction by p53 class mediator Inferred by curator PubMed 9878046. Source: BHF-UCL positive regulation of apoptotic process involved in mammary gland involution Inferred from mutant phenotype Ref.12. Source: MGI positive regulation of sequence-specific DNA binding transcription factor activity Inferred from mutant phenotype PubMed 19057511. Source: BHF-UCL positive regulation of transcription, DNA-dependent Inferred from mutant phenotype PubMed 19057511. Source: BHF-UCL protein K63-linked ubiquitination Inferred from sequence or structural similarity. Source: UniProtKB rRNA processing Inferred from electronic annotation. Source: UniProtKB-KW rRNA transcription Inferred from genetic interaction PubMed 18809582. Source: MGI regulation of nucleocytoplasmic transport Inferred from genetic interaction PubMed 15485902. Source: MGI regulation of protein stability Inferred from mutant phenotype Ref.11. Source: BHF-UCL somatic stem cell division Inferred from mutant phenotype PubMed 15964995. Source: HGNC somatic stem cell maintenance Inferred from genetic interaction PubMed 18957199. Source: MGI
Cellular_component	cytoplasm Inferred from direct assay Ref.11. Source: MGI granular component Inferred from direct assay Ref.11. Source: BHF-UCL mitochondrion Inferred from electronic annotation. Source: UniProtKB-SubCell nucleoplasm Inferred from direct assay Ref.11. Source: MGI
Molecular_function	DNA binding Inferred from electronic annotation. Source: UniProtKB-KW cyclin-dependent protein serine/threonine kinase inhibitor activity Inferred from direct assay PubMed 12130539 PubMed 7651726. Source: MGI sequence-specific DNA binding transcription factor activity Inferred from direct assay Ref.11. Source: MGI ubiquitin-protein ligase inhibitor activity Inferred from direct assay PubMed 9878046. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
C1QBP	Q07021	4	EBI-1202287,EBI-347528	From a different organism.
Pex19	Q8VCI5	4	EBI-1202306,EBI-1810767

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select] Note: Isoform 1 and isoform 3 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 3 Ref.1 (identifier: Q64364-1) Also known as: 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: P51480-1) Also known as: p16INK4a; The sequence of this isoform can be found in the external entry P51480. Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

Isoform 2 (identifier: P51480-2) The sequence of this isoform can be found in the external entry P51480. Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

Isoform 4 (identifier: Q64364-2) Also known as: smARF; The sequence of this isoform differs from the canonical sequence as follows: 1-44: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 169

169

Cyclin-dependent kinase inhibitor 2A, isoform 3

PRO_0000144182

Regions

Compositional bias

3 – 168

166

Arg-rich

Natural variations

Alternative sequence

1 – 44

Missing in isoform 4.

VSP_044963

Experimental info

Mutagenesis

L → P or R: No effect on activity. Ref.7

Mutagenesis

P → S: No effect on activity. Ref.7

Mutagenesis

R → Q: No effect on activity. Ref.7

Mutagenesis

105 – 106

Missing: No effect on activity. Ref.7

Mutagenesis

120

A → T: No effect on activity. Ref.7

Secondary structure

169

Helix Strand Turn

Details...

Sequences

Sequence

Length

Mass (Da)

Tools

Isoform 3 (p19ARF) (ARF) [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 644505EFE1CBF478
Show »

FASTA

169

19,238

        10         20         30         40         50         60 
MGRRFLVTVR IQRAGRPLQE RVFLVKFVRS RRPRTASCAL AFVNMLLRLE RILRRGPHRN 

        70         80         90        100        110        120 
PGPGDDDGQR SRSSSSAQLR CRFELRGPHY LLPPGARRSA GRLPGHAGGA ARVRGSAGCA 

       130        140        150        160 
RCLGSPAARL GPRAGTSRHR AIFAFRWVLF VFRWVVFVYR WERRPDRRA

« Hide

Isoform 1 (p16INK4a) [UniParc].

See P51480.

–

Isoform 2 [UniParc].

See P51480.

–

Isoform 4 (smARF) [UniParc].

Checksum: 84DD6C81A16E21F4
Show »

FASTA

125

14,096

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest." Quelle D.E., Zindy F., Ashmun R.A., Sherr C.J. Cell 83:993-1000(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: NMRI. Tissue: Mammary tumor.
[3]	"Characterization of the murine p19ARF promoter CpG island and its methylation pattern in primary lymphomas." Melendez B., Malumbres M., de Castro I.P., Santos J., Pellicer A., Fernandez-Piqueras J. Carcinogenesis 21:817-821(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-64. Strain: 129/SvJ.
[4]	"Sequence variation and chromosomal mapping of the murine Cdkn2a tumor suppressor gene." Herzog C.R., You M. Mamm. Genome 8:65-66(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-63. Strain: 020, 129/J, A/J, A/Wy, AKR/J, B10.A, B10.D2(58N), BALB/c, C3H/21BG, C3H/HeJ, C57BL/10SCN, C57BL/10SN, C57BL/6By, C57BL/6J, C57BR/cdJ, CBA/J, DBA/2J, HS/IBG, LP/J, LS/IBG, MA/M4J, PL/J, RF/J, Sencar, SJL/J, SM/J, ST/J and SWR/J. Tissue: Lung.
[5]	"Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1." Inoue K., Roussel M.F., Sherr C.J. Proc. Natl. Acad. Sci. U.S.A. 96:3993-3998(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-63. Strain: 129/SvjE.
[6]	"Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF." Kamijo T., Zindy F., Roussel M.F., Quelle D.E., Downing J.R., Ashmun R.A., Grosveld G., Sherr C.J. Cell 91:649-659(1997) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[7]	"Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF." Quelle D.E., Cheng M., Ashmun R.A., Sherr C.J. Proc. Natl. Acad. Sci. U.S.A. 94:669-673(1997) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF LEU-85; PRO-93; ARG-97; 105-GLY-HIS-106 AND ALA-120.
[8]	"The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53." Pomerantz J., Schreiber-Agus N., Liegeois N.J., Silverman A., Alland L., Chin L., Potes J., Chen K., Orlow I., Lee H.-W., Cordon-Cardo C., DePinho R.A. Cell 92:713-723(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH MDM2.
[9]	"P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2." Tao W., Levine A.J. Proc. Natl. Acad. Sci. U.S.A. 96:6937-6941(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[10]	"Disruption of the ARF transcriptional activator DMP1 facilitates cell immortalization, Ras transformation, and tumorigenesis." Inoue K., Wen R., Rehg J.E., Adachi M., Cleveland J.L., Roussel M.F., Sherr C.J. Genes Dev. 14:1797-1809(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[11]	"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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CDKN2AIP.
[12]	"p19ARF determines the balance between normal cell proliferation rate and apoptosis during mammary gland development." Yi Y., Shepard A., Kittrell F., Mulac-Jericevic B., Medina D., Said T.K. Mol. Biol. Cell 15:2302-2311(2004) [PubMed] [Europe PMC] [Abstract] Cited for: DEVELOPMENTAL STAGE, INDUCTION, DISRUPTION PHENOTYPE.
[13]	"p19ARF directly and differentially controls the functions of c-Myc independently of p53." Qi Y., Gregory M.A., Li Z., Brousal J.P., West K., Hann S.R. Nature 431:712-717(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH MYC.
[14]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH BCL6.
[15]	"Ras-Raf-Arf signaling critically depends on the Dmp1 transcription factor." Sreeramaneni R., Chaudhry A., McMahon M., Sherr C.J., Inoue K. Mol. Cell. Biol. 25:220-232(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INDUCTION.
[16]	"A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death." Reef S., Zalckvar E., Shifman O., Bialik S., Sabanay H., Oren M., Kimchi A. Mol. Cell 22:463-475(2006) [PubMed] [Europe PMC] [Abstract] Cited for: ALTERNATIVE SPLICING (ISOFORM 4), FUNCTION (ISOFORM 4), SUBCELLULAR LOCATION (ISOFORM 4).
[17]	"Mutually exclusive inactivation of DMP1 and ARF/p53 in lung cancer." Mallakin A., Sugiyama T., Taneja P., Matise L.A., Frazier D.P., Choudhary M., Hawkins G.A., D'Agostino R.B. Jr., Willingham M.C., Inoue K. Cancer Cell 12:381-394(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[18]	"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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TBRG1.
[19]	"The autophagic inducer smARF interacts with and is stabilized by the mitochondrial p32 protein." Reef S., Shifman O., Oren M., Kimchi A. Oncogene 26:6677-6683(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH C1QBP.
[20]	"Repression of Dmp1 and Arf transcription by anthracyclins: critical roles of the NF-kappaB subunit p65." Taneja P., Mallakin A., Matise L.A., Frazier D.P., Choudhary M., Inoue K. Oncogene 26:7457-7466(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[21]	"Solution structure of the p53 regulatory domain of the p19Arf tumor suppressor protein." DiGiammarino E.L., Filippov I., Weber J.D., Bothner B., Kriwacki R.W. Biochemistry 40:2379-2386(2001) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 1-37.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L76092 mRNA. Translation: AAC42080.1.
BC058190 mRNA. Translation: AAH58190.3.
S80650 mRNA. Translation: AAB35770.1.
AJ238890 Genomic DNA. Translation: CAB65598.1.
U49281 Genomic DNA. Translation: AAC00053.1.
U49282 Genomic DNA. Translation: AAC00054.1.
AF120108 Genomic DNA. Translation: AAD33245.1.

IPI

IPI00133446.

RefSeq

NP_034007.1. NM_009877.2.

UniGene

Mm.4733.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1HN3	NMR	-	A	1-37	[»]

DisProt

DP00335.

ProteinModelPortal

Q64364.

SMR

Q64364. Positions 1-37.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-24169N.

IntAct

Q64364. 6 interactions.

Proteomic databases

PRIDE

Q64364.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000030237; ENSMUSP00000030237; ENSMUSG00000044303.

GeneID

12578.

KEGG

mmu:12578.

UCSC

uc008toi.1. mouse.

Organism-specific databases

CTD

1029.

MGI

MGI:104738. Cdkn2a.

Phylogenomic databases

GeneTree

ENSGT00390000008249.

HOVERGEN

HBG081068.

InParanoid

Q64364.

K06621.

Gene expression databases

ArrayExpress

Q64364.

Bgee

Q64364.

CleanEx

MM_CDKN2A.

Genevestigator

Q64364.

GermOnline

ENSMUSG00000044303. Mus musculus.

Family and domain databases

InterPro

IPR010868. Cyclin_kinase-Inhib_2A.
[Graphical view]

PANTHER

PTHR21414. PTHR21414. 1 hit.

Pfam

PF07392. P19Arf_N. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q64364.

NextBio

281698.

SOURCE

Search...

Entry information

Entry name

CD2A2_MOUSE

Accession

Primary (citable) accession number: Q64364
Secondary accession number(s): Q4U255, Q9QXC7, Q9R051

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 11, 2005
Last sequence update:	November 1, 1996
Last modified:	May 1, 2013
This is version 103 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Relevant documents

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

Names·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Alternative products

Sequence annotation (Features)

Molecule processing

Regions

Natural variations

Experimental info

Secondary structure

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Gene expression databases

Family and domain databases

Other

Entry information

Relevant documents