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Protein

Cyclin-dependent kinase inhibitor 2A

Gene

Cdkn2a

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

Functioni

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.

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Cell cycle

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase inhibitor 2AImported
Alternative name(s):
Cyclin-dependent kinase 4 inhibitor A
Short name:
CDK4I
p16-INK4a
Short name:
p16-INK4
Gene namesi
Name:Cdkn2aImported
Synonyms:P16ink4a
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:104738. Cdkn2a.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: MGI
  • mitochondrion Source: MGI
  • nucleolus Source: MGI
  • nucleoplasm Source: MGI
  • nucleus Source: MGI
  • protein complex Source: MGI
  • senescence-associated heterochromatin focus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi64 – 641C → G or R: No effect on activity. 1 Publication
Mutagenesisi76 – 761D → N: Loss of activity. 1 Publication
Mutagenesisi84 – 852Missing : Loss of activity. 1 Publication

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 168168Cyclin-dependent kinase inhibitor 2APRO_0000144178Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei152 – 1521PhosphoserineBy similarity
Modified residuei164 – 1641PhosphoserineBy similarity

Post-translational modificationi

Phosphorylation seems to increase interaction with CDK4.By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

PRIDEiP51480.

PTM databases

PhosphoSiteiP51480.

Expressioni

Gene expression databases

BgeeiP51480.
CleanExiMM_CDKN2A.
ExpressionAtlasiP51480. baseline and differential.
GenevisibleiP51480. MM.

Interactioni

Subunit structurei

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).By similarity

Protein-protein interaction databases

BioGridi198654. 34 interactions.
DIPiDIP-60251N.

Structurei

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1LNNmodel-A12-159[»]
ProteinModelPortaliP51480.
SMRiP51480. Positions 2-126.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Repeati3 – 3230ANK 1Add
BLAST
Repeati36 – 6429ANK 2Add
BLAST
Repeati69 – 9830ANK 3Add
BLAST
Repeati102 – 13130ANK 4Add
BLAST

Sequence similaritiesi

Contains 4 ANK repeats.Curated

Keywords - Domaini

ANK repeat, Repeat

Phylogenomic databases

eggNOGiNOG42176.
GeneTreeiENSGT00390000008249.
HOVERGENiHBG050870.
KOiK06621.
OMAiADSNCED.
OrthoDBiEOG7TTQ94.
TreeFamiTF352389.

Family and domain databases

Gene3Di1.25.40.20. 1 hit.
InterProiIPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
[Graphical view]
PfamiPF00023. Ank. 1 hit.
PF12796. Ank_2. 1 hit.
[Graphical view]
SMARTiSM00248. ANK. 4 hits.
[Graphical view]
SUPFAMiSSF48403. SSF48403. 1 hit.
PROSITEiPS50297. ANK_REP_REGION. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Isoform 1 and isoform tumor suppressor ARF 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) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MESAADRLAR AAAQGRVHDV RALLEAGVSP NAPNSFGRTP IQVMMMGNVH
60 70 80 90 100
VAALLLNYGA DSNCEDPTTF SRPVHDAARE GFLDTLVVLH GSGARLDVRD
110 120 130 140 150
AWGRLPLDLA QERGHQDIVR YLRSAGCSLC SAGWSLCTAG NVAQTDGHSF
160
SSSTPRALEL RGQSQEQS
Length:168
Mass (Da):17,941
Last modified:October 25, 2005 - v2
Checksum:i9A6B0F24F34D5FEC
GO
Isoform 2 (identifier: P51480-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-43: Missing.

Show »
Length:125
Mass (Da):13,458
Checksum:i97BE6143D7C8542D
GO
Isoform tumor suppressor ARF (identifier: Q64364-1) [UniParc]FASTAAdd to basket

Also known as: p19ARF

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.
Length:169
Mass (Da):19,238
GO
Isoform smARF (identifier: Q64364-2) [UniParc]FASTAAdd to basket

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.
Length:125
Mass (Da):14,096
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti11 – 111Missing in AAA85453 (PubMed:7651726).Curated

Polymorphismi

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

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti12 – 121A → V in some liver tumors. 1 Publication
Natural varianti18 – 181H → P in strain: 020, BALB/c, BALB/cJ, C3H/21BG, C3H/HeJ, CBA/J, MA/M4J and PL/J. 3 Publications
Natural varianti27 – 271G → E in some liver tumors. 1 Publication
Natural varianti51 – 511V → I in strain: BALB/c and BALB/cJ. 2 Publications
Natural varianti73 – 731P → L in some liver tumors. 1 Publication
Natural varianti74 – 741V → M in plasmacytoma cell lines. 1 Publication
Natural varianti75 – 751H → Y in plasmacytoma cell lines. 1 Publication
Natural varianti90 – 901H → Q in strain: BALB/cJ, C57BL/6J and MOLF/Ei. 1 Publication
Natural varianti90 – 901H → R in plasmacytoma cell lines. 1 Publication
Natural varianti127 – 1271C → S in strain: BALB/cJ, C57BL/6J and MOLF/Ei. 1 Publication

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 4343Missing in isoform 2. CuratedVSP_015867Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS38812.1. [P51480-1]
RefSeqiNP_001035744.1. NM_001040654.1. [P51480-1]
UniGeneiMm.4733.

Genome annotation databases

EnsembliENSMUST00000060501; ENSMUSP00000061847; ENSMUSG00000044303. [P51480-1]
GeneIDi12578.
KEGGimmu:12578.
UCSCiuc008toh.1. mouse. [P51480-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS38812.1. [P51480-1]
RefSeqiNP_001035744.1. NM_001040654.1. [P51480-1]
UniGeneiMm.4733.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1LNNmodel-A12-159[»]
ProteinModelPortaliP51480.
SMRiP51480. Positions 2-126.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198654. 34 interactions.
DIPiDIP-60251N.

PTM databases

PhosphoSiteiP51480.

Proteomic databases

PRIDEiP51480.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000060501; ENSMUSP00000061847; ENSMUSG00000044303. [P51480-1]
GeneIDi12578.
KEGGimmu:12578.
UCSCiuc008toh.1. mouse. [P51480-1]

Organism-specific databases

CTDi1029.
MGIiMGI:104738. Cdkn2a.

Phylogenomic databases

eggNOGiNOG42176.
GeneTreeiENSGT00390000008249.
HOVERGENiHBG050870.
KOiK06621.
OMAiADSNCED.
OrthoDBiEOG7TTQ94.
TreeFamiTF352389.

Miscellaneous databases

NextBioi281698.
SOURCEiSearch...

Gene expression databases

BgeeiP51480.
CleanExiMM_CDKN2A.
ExpressionAtlasiP51480. baseline and differential.
GenevisibleiP51480. MM.

Family and domain databases

Gene3Di1.25.40.20. 1 hit.
InterProiIPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
[Graphical view]
PfamiPF00023. Ank. 1 hit.
PF12796. Ank_2. 1 hit.
[Graphical view]
SMARTiSM00248. ANK. 4 hits.
[Graphical view]
SUPFAMiSSF48403. SSF48403. 1 hit.
PROSITEiPS50297. ANK_REP_REGION. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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.
    , 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. 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.

Entry informationi

Entry nameiCDN2A_MOUSE
AccessioniPrimary (citable) accession number: P51480
Secondary accession number(s): A2ANM1
, A2ANM2, O89088, P97510, P97937, Q6PEA2, Q78E39, Q78E57, Q792X7, Q9QWH6, Q9QWH7, Q9QWH8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 25, 2005
Last modified: July 22, 2015
This is version 136 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Caution

The proteins described here are encoded by the gene CDKN2A, but are completely unrelated in term of sequence and function to tumor suppressor ARF (AC Q64364) which is encoded by the same gene.Curated

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
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.