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Q64364

- CD2A2_MOUSE

UniProt

Q64364 - CD2A2_MOUSE

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Protein

Cyclin-dependent kinase inhibitor 2A, isoform 3

Gene

Cdkn2a

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.By similarity8 Publications

GO - Molecular functioni

  1. cyclin-dependent protein serine/threonine kinase inhibitor activity Source: MGI
  2. DNA binding Source: UniProtKB-KW
  3. sequence-specific DNA binding transcription factor activity Source: MGI
  4. ubiquitin-protein transferase inhibitor activity Source: BHF-UCL

GO - Biological processi

  1. aging Source: MGI
  2. apoptotic process Source: UniProtKB-KW
  3. cell aging Source: MGI
  4. cell cycle arrest Source: MGI
  5. cellular response to hydrogen peroxide Source: MGI
  6. cellular senescence Source: MGI
  7. epidermis development Source: MGI
  8. glucose homeostasis Source: MGI
  9. negative regulation of B cell proliferation Source: HGNC
  10. negative regulation of cell cycle Source: MGI
  11. negative regulation of cell growth Source: BHF-UCL
  12. negative regulation of cyclin-dependent protein serine/threonine kinase activity Source: MGI
  13. negative regulation of immature T cell proliferation in thymus Source: HGNC
  14. negative regulation of mammary gland epithelial cell proliferation Source: MGI
  15. negative regulation of ubiquitin-protein transferase activity Source: BHF-UCL
  16. positive regulation of apoptotic process involved in mammary gland involution Source: MGI
  17. positive regulation of DNA damage response, signal transduction by p53 class mediator Source: BHF-UCL
  18. positive regulation of sequence-specific DNA binding transcription factor activity Source: BHF-UCL
  19. positive regulation of transcription, DNA-templated Source: BHF-UCL
  20. protein K63-linked ubiquitination Source: UniProtKB
  21. protein polyubiquitination Source: UniProtKB
  22. regulation of cyclin-dependent protein serine/threonine kinase activity Source: MGI
  23. regulation of gene expression Source: MGI
  24. regulation of nucleocytoplasmic transport Source: MGI
  25. regulation of protein stability Source: BHF-UCL
  26. regulation of transcription, DNA-templated Source: MGI
  27. rRNA processing Source: UniProtKB-KW
  28. rRNA transcription Source: MGI
  29. somatic stem cell division Source: HGNC
  30. somatic stem cell maintenance Source: MGI
Complete GO annotation...

Keywords - Biological processi

Apoptosis, Cell cycle, rRNA processing, Transcription, Transcription regulation, Ubl conjugation pathway

Keywords - Ligandi

DNA-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase inhibitor 2A, isoform 3
Alternative name(s):
p19ARF
Gene namesi
Name:Cdkn2aImported
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 4

Organism-specific databases

MGIiMGI:104738. Cdkn2a.

Subcellular locationi

Nucleusnucleolus 4 Publications. Nucleusnucleoplasm By similarity
Isoform 4 : Mitochondrion 1 Publication

GO - Cellular componenti

  1. cytoplasm Source: MGI
  2. granular component Source: BHF-UCL
  3. mitochondrion Source: UniProtKB-KW
  4. nucleolus Source: MGI
  5. nucleoplasm Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Mitochondrion, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice lacking isoform p19ARF of Cdkn2a display delayed mammary gland involution.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi85 – 851L → P or R: No effect on activity. 1 Publication
Mutagenesisi93 – 931P → S: No effect on activity. 1 Publication
Mutagenesisi97 – 971R → Q: No effect on activity. 1 Publication
Mutagenesisi105 – 1062Missing: No effect on activity. 1 Publication
Mutagenesisi120 – 1201A → T: No effect on activity. 1 Publication

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 169169Cyclin-dependent kinase inhibitor 2A, isoform 3PRO_0000144182Add
BLAST

Post-translational modificationi

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).By similarity

Keywords - PTMi

Ubl conjugation

Proteomic databases

MaxQBiQ64364.
PRIDEiQ64364.

Expressioni

Developmental stagei

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 15.1 Publication

Inductioni

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).4 Publications

Gene expression databases

BgeeiQ64364.
CleanExiMM_CDKN2A.
ExpressionAtlasiQ64364. baseline and differential.
GenevestigatoriQ64364.

Interactioni

Subunit structurei

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.By similarity6 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
C1QBPQ070214EBI-1202287,EBI-347528From a different organism.
Pex19Q8VCI54EBI-1202306,EBI-1810767

Protein-protein interaction databases

BioGridi198654. 34 interactions.
DIPiDIP-24169N.
IntActiQ64364. 6 interactions.
MINTiMINT-193442.

Structurei

Secondary structure

1
169
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi4 – 1411
Helixi20 – 2910

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1HN3NMR-A1-37[»]
DisProtiDP00335.
ProteinModelPortaliQ64364.
SMRiQ64364. Positions 1-37.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ64364.

Family & Domainsi

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi3 – 168166Arg-richSequence AnalysisAdd
BLAST

Phylogenomic databases

GeneTreeiENSGT00390000008249.
HOVERGENiHBG081068.
InParanoidiQ64364.
KOiK06621.
OMAiRTASCAL.
PhylomeDBiQ64364.

Family and domain databases

InterProiIPR010868. Cyclin_kinase-Inhib_2A.
[Graphical view]
PfamiPF07392. P19Arf_N. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. Align

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.1 Publication

Isoform 31 Publication (identifier: Q64364-1) [UniParc]FASTAAdd to Basket

Also known as: p19ARF1 Publication

, ARF1 Publication

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.

« Hide

        10         20         30         40         50
MGRRFLVTVR IQRAGRPLQE RVFLVKFVRS RRPRTASCAL AFVNMLLRLE
60 70 80 90 100
RILRRGPHRN PGPGDDDGQR SRSSSSAQLR CRFELRGPHY LLPPGARRSA
110 120 130 140 150
GRLPGHAGGA ARVRGSAGCA RCLGSPAARL GPRAGTSRHR AIFAFRWVLF
160
VFRWVVFVYR WERRPDRRA
Length:169
Mass (Da):19,238
Last modified:November 1, 1996 - v1
Checksum:i644505EFE1CBF478
GO
Isoform 1Curated (identifier: P51480-1) [UniParc]FASTAAdd to Basket

Also known as: p16INK4aCurated

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.
Length:168
Mass (Da):17,941
GO
Isoform 2Curated (identifier: P51480-2) [UniParc]FASTAAdd to Basket

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.
Length:125
Mass (Da):13,458
GO
Isoform 4 (identifier: Q64364-2) [UniParc]FASTAAdd to Basket

Also known as: smARF

The sequence of this isoform differs from the canonical sequence as follows:
     1-44: Missing.

Show »
Length:125
Mass (Da):14,096
Checksum:i84DD6C81A16E21F4
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 4444Missing in isoform 4. CuratedVSP_044963Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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.
CCDSiCCDS18350.1. [Q64364-1]
RefSeqiNP_034007.1. NM_009877.2. [Q64364-1]
UniGeneiMm.4733.

Genome annotation databases

EnsembliENSMUST00000107131; ENSMUSP00000102748; ENSMUSG00000044303. [Q64364-1]
GeneIDi12578.
KEGGimmu:12578.
UCSCiuc008toi.1. mouse. [Q64364-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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 .
CCDSi CCDS18350.1. [Q64364-1 ]
RefSeqi NP_034007.1. NM_009877.2. [Q64364-1 ]
UniGenei Mm.4733.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
1HN3 NMR - A 1-37 [» ]
DisProti DP00335.
ProteinModelPortali Q64364.
SMRi Q64364. Positions 1-37.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 198654. 34 interactions.
DIPi DIP-24169N.
IntActi Q64364. 6 interactions.
MINTi MINT-193442.

Proteomic databases

MaxQBi Q64364.
PRIDEi Q64364.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000107131 ; ENSMUSP00000102748 ; ENSMUSG00000044303 . [Q64364-1 ]
GeneIDi 12578.
KEGGi mmu:12578.
UCSCi uc008toi.1. mouse. [Q64364-1 ]

Organism-specific databases

CTDi 1029.
MGIi MGI:104738. Cdkn2a.

Phylogenomic databases

GeneTreei ENSGT00390000008249.
HOVERGENi HBG081068.
InParanoidi Q64364.
KOi K06621.
OMAi RTASCAL.
PhylomeDBi Q64364.

Miscellaneous databases

EvolutionaryTracei Q64364.
NextBioi 281698.
SOURCEi Search...

Gene expression databases

Bgeei Q64364.
CleanExi MM_CDKN2A.
ExpressionAtlasi Q64364. baseline and differential.
Genevestigatori Q64364.

Family and domain databases

InterProi IPR010868. Cyclin_kinase-Inhib_2A.
[Graphical view ]
Pfami PF07392. P19Arf_N. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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/SvJImported.
  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: 0201 Publication, 129/JImported, A/JImported, A/WyImported, AKR/JImported, B10.AImported, B10.D2(58N)Imported, BALB/c1 Publication, C3H/21BG1 Publication, C3H/HeJ1 Publication, C57BL/10SCNImported, C57BL/10SNImported, C57BL/6ByImported, C57BL/6J1 Publication, C57BR/cdJImported, CBA/J1 Publication, DBA/2JImported, HS/IBGImported, LP/JImported, LS/IBGImported, MA/M4JImported, PL/J1 Publication, RF/JImported, Sencar1 Publication, SJL/JImported, SM/JImported, ST/JImported and SWR/JImported.
    Tissue: Lung1 Publication.
  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/SvjEImported.
  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. Cited for: FUNCTION.
  18. 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.

Entry informationi

Entry nameiCD2A2_MOUSE
AccessioniPrimary (citable) accession number: Q64364
Secondary accession number(s): Q4U255, Q9QXC7, Q9R051
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 11, 2005
Last sequence update: November 1, 1996
Last modified: October 29, 2014
This is version 117 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references

External Data

Dasty 3