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Q64364 (CD2A2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 114. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cyclin-dependent kinase inhibitor 2A, isoform 3
Alternative name(s):
p19ARF
Gene names
Name:Cdkn2a
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length169 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 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 isstabilized 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

Nucleusnucleolus. Nucleusnucleoplasm 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 p19ARFof Cdkn2a display delayed mammary gland involution. Ref.12

Ontologies

Keywords
   Biological processApoptosis
Cell cycle
rRNA processing
Transcription
Transcription regulation
Ubl conjugation pathway
   Cellular componentMitochondrion
Nucleus
   Coding sequence diversityAlternative splicing
   DiseaseTumor suppressor
   LigandDNA-binding
   PTMUbl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processaging

Inferred from mutant phenotype PubMed 11551927. Source: MGI

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

cellular response to hydrogen peroxide

Inferred from direct assay PubMed 20808772. 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 cycle

Inferred from direct assay PubMed 15485902. Source: MGI

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 transferase 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-templated

Inferred from mutant phenotype PubMed 19057511. Source: BHF-UCL

protein K63-linked ubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

protein polyubiquitination

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 cyclin-dependent protein serine/threonine kinase activity

Inferred from direct assay PubMed 7651726. Source: MGI

regulation of gene expression

Inferred from mutant phenotype PubMed 11438662. 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

regulation of transcription, DNA-templated

Inferred from direct assay Ref.11. Source: MGI

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_componentcytoplasm

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

nucleolus

Inferred from direct assay PubMed 11718560Ref.11PubMed 15485902Ref.14PubMed 15989966PubMed 16199867. Source: MGI

nucleoplasm

Inferred from direct assay Ref.11. Source: MGI

   Molecular_functionDNA binding

Inferred from electronic annotation. Source: UniProtKB-KW

cyclin-dependent protein serine/threonine kinase inhibitor activity

Inferred from direct assay PubMed 12130539PubMed 7651726. Source: MGI

protein binding

Inferred from physical interaction PubMed 11259404Ref.19. Source: IntAct

sequence-specific DNA binding transcription factor activity

Inferred from direct assay Ref.11. Source: MGI

ubiquitin-protein transferase inhibitor activity

Inferred from direct assay PubMed 9878046. Source: BHF-UCL

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

C1QBPQ070214EBI-1202287,EBI-347528From a different organism.
Pex19Q8VCI54EBI-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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 169169Cyclin-dependent kinase inhibitor 2A, isoform 3
PRO_0000144182

Regions

Compositional bias3 – 168166Arg-rich

Natural variations

Alternative sequence1 – 4444Missing in isoform 4.
VSP_044963

Experimental info

Mutagenesis851L → P or R: No effect on activity. Ref.7
Mutagenesis931P → S: No effect on activity. Ref.7
Mutagenesis971R → Q: No effect on activity. Ref.7
Mutagenesis105 – 1062Missing: No effect on activity. Ref.7
Mutagenesis1201A → T: No effect on activity. Ref.7

Secondary structure

..... 169
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 3 (p19ARF) (ARF) [UniParc].

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

FASTA16919,238
        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 »

FASTA12514,096

References

« Hide '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.
CCDSCCDS18350.1. [Q64364-1]
RefSeqNP_034007.1. NM_009877.2. [Q64364-1]
UniGeneMm.4733.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1HN3NMR-A1-37[»]
DisProtDP00335.
ProteinModelPortalQ64364.
SMRQ64364. Positions 1-37.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198654. 34 interactions.
DIPDIP-24169N.
IntActQ64364. 6 interactions.
MINTMINT-193442.

Proteomic databases

PRIDEQ64364.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000107131; ENSMUSP00000102748; ENSMUSG00000044303. [Q64364-1]
GeneID12578.
KEGGmmu:12578.
UCSCuc008toi.1. mouse. [Q64364-1]

Organism-specific databases

CTD1029.
MGIMGI:104738. Cdkn2a.

Phylogenomic databases

GeneTreeENSGT00390000008249.
HOVERGENHBG081068.
InParanoidQ64364.
KOK06621.
OMARTASCAL.
PhylomeDBQ64364.

Gene expression databases

ArrayExpressQ64364.
BgeeQ64364.
CleanExMM_CDKN2A.
GenevestigatorQ64364.

Family and domain databases

InterProIPR010868. Cyclin_kinase-Inhib_2A.
[Graphical view]
PfamPF07392. P19Arf_N. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ64364.
NextBio281698.
SOURCESearch...

Entry information

Entry nameCD2A2_MOUSE
AccessionPrimary (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: July 9, 2014
This is version 114 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

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