Reviewed, UniProtKB/Swiss-Prot Q64364 (CD2A2_MOUSE)

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)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › 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 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.1 Ref.6 Ref.8 Ref.9 Ref.13 Ref.14 Ref.15 Ref.16 Ref.12 UniProtKB Q8N726
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.8 Ref.13 Ref.14 Ref.11 Ref.17 UniProtKB Q8N726
Subcellular location	Nucleus › nucleolus Ref.1 Ref.9 Ref.14 Ref.15.
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.15 Ref.12 Ref.10 Ref.18
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 rRNA processing
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Disease	Tumor suppressor
Ligand	DNA-binding
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cell aging Inferred from direct assay. Source: MGI cell cycle arrest Inferred from direct assay. Source: MGI epidermis development Inferred from mutant phenotype. Source: MGI negative regulation of B cell proliferation Inferred from mutant phenotype. Source: HGNC negative regulation of cell growth Ref.11 Inferred from mutant phenotype. Source: UniProtKB negative regulation of cyclin-dependent protein kinase activity Inferred from direct assay. Source: MGI negative regulation of immature T cell proliferation in the thymus Inferred from mutant phenotype. Source: HGNC negative regulation of mammary gland epithelial cell proliferation Ref.12 Inferred from mutant phenotype. Source: MGI negative regulation of ubiquitin-protein ligase activity Inferred from direct assay. Source: UniProtKB positive regulation of DNA damage response, signal transduction by p53 class mediator Inferred by curator. Source: UniProtKB positive regulation of apoptosis involved in mammary gland involution Ref.12 Inferred from mutant phenotype. Source: MGI rRNA processing Inferred from electronic annotation. Source: UniProtKB-KW rRNA transcription Inferred from genetic interaction. Source: MGI regulation of nucleocytoplasmic transport Inferred from genetic interaction. Source: MGI regulation of protein stability Ref.11 Inferred from mutant phenotype. Source: UniProtKB regulation of transcription, DNA-dependent Ref.11 Inferred from direct assay. Source: MGI somatic stem cell division Inferred from mutant phenotype. Source: HGNC
Cellular component	cytoplasm Ref.11 Inferred from direct assay. Source: MGI granular component Ref.11 Inferred from direct assay. Source: UniProtKB nucleoplasm Ref.11 Inferred from direct assay. Source: MGI
Molecular function	cyclin-dependent protein kinase inhibitor activity Inferred from direct assay. Source: MGI protein binding Inferred from physical interaction. Source: IntAct transcription factor activity Ref.11 Inferred from direct assay. Source: MGI ubiquitin-protein ligase inhibitor activity Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Pex19	Q8VCI5	1	EBI-1202306,EBI-1810767
Ppp1ca	P62137	1	EBI-1202287,EBI-357187
Ppp1cc	P63087-1	1	EBI-1202287,EBI-450267

Alternative products

This entry describes 3 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 P51480-1.
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 P51480-2.
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 – 169

169

Cyclin-dependent kinase inhibitor 2A, isoform 3

PRO_0000144182

Regions

Compositional bias

3 – 168

166

Arg-rich

Experimental info

Mutagenesis

85

1

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

Mutagenesis

93

1

P → S: No effect on activity. Ref.7

Mutagenesis

97

1

R → Q: No effect on activity. Ref.7

Mutagenesis

105 – 106

2

Missing: No effect on activity. Ref.7

Mutagenesis

120

1

A → T: No effect on activity. Ref.7

Secondary structure

1

.

.

.

.

.

169

Helix Strand Turn

Details...

Helix

4 – 14

11

Helix

20 – 29

10

Sequences

	Sequence		Length	Mass (Da)
	Isoform 3 (p19ARF) (ARF) [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 644505EFE1CBF478	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
	Isoform 1 (p16INK4a). See P51480.	FASTA	–	–
	Isoform 2. See P51480.	FASTA	–	–

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: 8521522] [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: 15489334] [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: 10753221] [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: 9021155] [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: 10097151] [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: 9393858] [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: 9012842] [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: 9529248] [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: 10359817] [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: 10898794] [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: 12154087] [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: 15105443] [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: 15361884] [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: 15567177] [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: 15601844] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INDUCTION.
[16]	"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: 17936562] [Abstract] Cited for: FUNCTION.
[17]	"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.
[18]	"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: 17546045] [Abstract] Cited for: INDUCTION.
[19]	"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: 11327858] [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.

UniGene

Mm.4733

3D structure databases

PDBe
RCSB PDB
PDBj

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

DisProt

DP00335.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-24169N.

IntAct

Q64364. 4 interactions.

STRING

Q64364.

Proteomic databases

PRIDE

Q64364.

Genome annotation databases

Ensembl

ENSMUST00000030237; ENSMUSP00000030237; ENSMUSG00000044303; Mus musculus. [Genome view]

GeneID

12578.

UCSC

uc008toi.1. mouse.

Organism-specific databases

CTD

12578.

MGI

MGI:104738. Cdkn2a.

Phylogenomic databases

HOVERGEN

Q64364.

InParanoid

Q64364.

OrthoDB

EOG9N5ZK9.

Gene expression databases

ArrayExpress

Q64364.

Bgee

Q64364.

CleanEx

MM_CDKN2A.

Genevestigator

Q64364.

GermOnline

ENSMUSG00000044303. Mus musculus.

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

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:	December 15, 2009
This is version 74 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)