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P51480 (CD2A1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 122. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cyclin-dependent kinase inhibitor 2A, isoforms 1/2
Alternative name(s):
Cyclin-dependent kinase 4 inhibitor A
Short name=CDK4I
p16-INK4a
Short name=p16-INK4
Gene names
Name:Cdkn2a
Synonyms:P16ink4a
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length168 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein.

Subunit structure

Heterodimer with CDK4 or CDK6. Predominamt P16 complexes contained CDK6. Interacts with CDK4 (both 'T-172'-phosphorylated and non-phosphorylated forms); the interaction inhibits cyclin D-CDK4 kinase activity. Interacts with ISCO2 By similarity.

Subcellular location

Cytoplasm By similarity. Nucleus By similarity.

Post-translational modification

Phosphorylation seems to increase interaction with CDK4 By similarity.

Polymorphism

Strain BALB/c displays a significantly reduced ability to inhibit phosphorylation of the retinoblastoma protein.

Sequence similarities

Belongs to the CDKN2 cyclin-dependent kinase inhibitor family.

Contains 4 ANK repeats.

Ontologies

Keywords
   Biological processCell cycle
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseTumor suppressor
   DomainANK repeat
Repeat
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processaging

Inferred from mutant phenotype PubMed 11551927. Source: MGI

cell aging

Inferred from direct assay PubMed 11748239. Source: MGI

cell cycle arrest

Inferred from direct assay Ref.1. 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 cell cycle

Inferred from direct assay PubMed 15485902. Source: MGI

negative regulation of cyclin-dependent protein serine/threonine kinase activity

Inferred from direct assay PubMed 12130539. Source: MGI

negative regulation of mammary gland epithelial cell proliferation

Inferred from mutant phenotype PubMed 15105443. Source: MGI

positive regulation of apoptotic process involved in mammary gland involution

Inferred from mutant phenotype PubMed 15105443. Source: MGI

positive regulation of macrophage apoptotic process

Inferred from genetic interaction PubMed 20381282. Source: BHF-UCL

positive regulation of smooth muscle cell apoptotic process

Inferred from genetic interaction PubMed 20381282. Source: BHF-UCL

rRNA transcription

Inferred from genetic interaction PubMed 18809582. Source: MGI

regulation of cyclin-dependent protein serine/threonine kinase activity

Inferred from direct assay Ref.1. 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 transcription, DNA-templated

Inferred from direct assay PubMed 12154087. Source: MGI

somatic stem cell maintenance

Inferred from genetic interaction PubMed 18957199. Source: MGI

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 12154087. Source: MGI

nucleolus

Inferred from direct assay PubMed 11718560PubMed 12154087PubMed 15485902PubMed 15567177PubMed 15989966PubMed 16199867. Source: MGI

nucleoplasm

Inferred from direct assay PubMed 12154087. Source: MGI

   Molecular_functioncyclin-dependent protein serine/threonine kinase inhibitor activity

Inferred from direct assay PubMed 12130539Ref.1. Source: MGI

sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 12154087. Source: MGI

Complete GO annotation...

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 1 (identifier: P51480-1)

Also known as: p16INK4a;

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 2 (identifier: P51480-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-43: Missing.
Isoform 3 (identifier: Q64364-1)

Also known as: p19ARF; ARF;

The sequence of this isoform can be found in the external entry Q64364.
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 can be found in the external entry Q64364.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 168168Cyclin-dependent kinase inhibitor 2A, isoforms 1/2
PRO_0000144178

Regions

Repeat3 – 3230ANK 1
Repeat36 – 6429ANK 2
Repeat69 – 9830ANK 3
Repeat102 – 13130ANK 4

Amino acid modifications

Modified residue1521Phosphoserine By similarity
Modified residue1641Phosphoserine By similarity

Natural variations

Alternative sequence1 – 4343Missing in isoform 2.
VSP_015867
Natural variant121A → V in some liver tumors. Ref.9
Natural variant181H → P in strain: 020, BALB/c, BALB/cJ, C3H/21BG, C3H/HeJ, CBA/J, MA/M4J and PL/J. Ref.2 Ref.7 Ref.8
Natural variant271G → E in some liver tumors. Ref.9
Natural variant511V → I in strain: BALB/c and BALB/cJ. Ref.2 Ref.7
Natural variant731P → L in some liver tumors. Ref.9
Natural variant741V → M in plasmacytoma cell lines. Ref.2
Natural variant751H → Y in plasmacytoma cell lines. Ref.2
Natural variant901H → Q in strain: BALB/cJ, C57BL/6J and MOLF/Ei. Ref.7
Natural variant901H → R in plasmacytoma cell lines. Ref.2
Natural variant1271C → S in strain: BALB/cJ, C57BL/6J and MOLF/Ei. Ref.7

Experimental info

Mutagenesis641C → G or R: No effect on activity. Ref.10
Mutagenesis761D → N: Loss of activity. Ref.10
Mutagenesis84 – 852Missing: Loss of activity.
Sequence conflict111Missing in AAA85453. Ref.1

Secondary structure

...................... 168
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (p16INK4a) [UniParc].

Last modified October 25, 2005. Version 2.
Checksum: 9A6B0F24F34D5FEC

FASTA16817,941
        10         20         30         40         50         60 
MESAADRLAR AAAQGRVHDV RALLEAGVSP NAPNSFGRTP IQVMMMGNVH VAALLLNYGA 

        70         80         90        100        110        120 
DSNCEDPTTF SRPVHDAARE GFLDTLVVLH GSGARLDVRD AWGRLPLDLA QERGHQDIVR 

       130        140        150        160 
YLRSAGCSLC SAGWSLCTAG NVAQTDGHSF SSSTPRALEL RGQSQEQS 

« Hide

Isoform 2 [UniParc].

Checksum: 97BE6143D7C8542D
Show »

FASTA12513,458
Isoform 3 (p19ARF) (ARF) [UniParc].

See Q64364.

Isoform 4 (smARF) [UniParc].

See Q64364.

References

« Hide 'large scale' references
[1]"Cloning and characterization of murine p16INK4a and p15INK4b genes."
Quelle D.E., Ashmun R.A., Hannon G.J., Rehberger P.A., Trono D., Richter K.H., Walker C., Beach D., Sherr C.J., Serrano M.
Oncogene 11:635-645(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]"Cdkn2a, the cyclin-dependent kinase inhibitor encoding p16(INK4a) and p19(ARF), is a candidate for the plasmacytoma susceptibility locus, Pctr1."
Zhang S., Ramsay E.S., Mock B.A.
Proc. Natl. Acad. Sci. U.S.A. 95:2429-2434(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS PRO-18; ILE-51; MET-74; TYR-75 AND ARG-90.
Strain: BALB/c and DBA/2N.
Tissue: Spleen.
[3]"Cloning and structure analysis of murine p16INK4a."
Gong Z., Li J., Fu J.
Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Strain: 129/SvJ.
[4]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[5]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6J.
[6]"Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas."
Malumbres M., de Castro I.P., Santos J., Melendez B., Mangues R., Serrano M., Pellicer A., Fernandez-Piqueras J.
Oncogene 14:1361-1370(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-155.
Strain: C57BL/6J X DBA.
[7]"Comparative analysis of the p16(INK4a) and p15(INK4b) DNA sequences in mouse inbred strains."
Santos J., Melendez B., Perez de Castro I., Malumbres M., Serrano M., Pellicer A., Fernandez-Piqueras J.
Submitted (OCT-1996) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-155, VARIANTS PRO-18; ILE-51; GLN-90 AND SER-127.
Strain: BALB/cJ, C57BL/6J, CAST/Ei, MOLF/Ei and RF/J.
[8]"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 [MRNA] OF 1-42 (ISOFORM 1), VARIANT PRO-18.
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.
[9]"Induction of mutations in Ki-ras and INK4a in liver tumors of mice exposed in utero to 3-methylcholanthrene."
Gressani K.M., Rollins L.A., Leone-Kabler S., Cline J.M., Miller M.S.
Carcinogenesis 19:1045-1052(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-42, VARIANTS VAL-12; GLU-27 AND LEU-73.
[10]"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 CYS-64; ASP-76 AND 84-ASP-THR-85.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L76150 mRNA. Translation: AAA85453.1.
AF044335 mRNA. Translation: AAC08962.1.
AF044336 mRNA. Translation: AAC08963.1.
AF332190 Genomic DNA. Translation: AAK83159.1.
AK155307 mRNA. Translation: BAE33180.1.
AL831719 Genomic DNA. Translation: CAM16002.1.
AL831719 Genomic DNA. Translation: CAM16003.1.
U66087, U66086 Genomic DNA. Translation: AAB39600.1.
U79625 Genomic DNA. Translation: AAD00223.1.
U79626 Genomic DNA. Translation: AAD00224.1.
U79627 Genomic DNA. Translation: AAD00225.1.
U79628 Genomic DNA. Translation: AAD00226.1.
U79630 Genomic DNA. Translation: AAD00227.1.
U79631 Genomic DNA. Translation: AAD00228.1.
U79632 Genomic DNA. Translation: AAD00229.1.
U49279 Genomic DNA. Translation: AAC00051.1.
U49280 Genomic DNA. Translation: AAC00052.1.
AF004588 Genomic DNA. Translation: AAB61416.1.
RefSeqNP_001035744.1. NM_001040654.1.
UniGeneMm.4733.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1LNNmodel-A12-159[»]
ProteinModelPortalP51480.
SMRP51480. Positions 2-126.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198654. 34 interactions.
DIPDIP-60251N.

PTM databases

PhosphoSiteP51480.

Proteomic databases

PRIDEP51480.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000060501; ENSMUSP00000061847; ENSMUSG00000044303. [P51480-1]
GeneID12578.
KEGGmmu:12578.
UCSCuc008toh.1. mouse. [P51480-1]

Organism-specific databases

CTD1029.
MGIMGI:104738. Cdkn2a.

Phylogenomic databases

eggNOGNOG42176.
GeneTreeENSGT00390000008249.
HOVERGENHBG050870.
KOK06621.
OMAADSNCED.
OrthoDBEOG7TTQ94.
TreeFamTF352389.

Gene expression databases

ArrayExpressP51480.
BgeeP51480.
CleanExMM_CDKN2A.
GenevestigatorP51480.

Family and domain databases

Gene3D1.25.40.20. 1 hit.
InterProIPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
[Graphical view]
PfamPF00023. Ank. 1 hit.
PF12796. Ank_2. 1 hit.
[Graphical view]
SMARTSM00248. ANK. 4 hits.
[Graphical view]
SUPFAMSSF48403. SSF48403. 1 hit.
PROSITEPS50297. ANK_REP_REGION. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio281698.
SOURCESearch...

Entry information

Entry nameCD2A1_MOUSE
AccessionPrimary (citable) accession number: P51480
Secondary accession number(s): A2ANM1 expand/collapse secondary AC list , A2ANM2, O89088, P97510, P97937, Q6PEA2, Q78E39, Q78E57, Q792X7, Q9QWH6, Q9QWH7, Q9QWH8
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 25, 2005
Last modified: April 16, 2014
This is version 122 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

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