ID CDN2A_MOUSE Reviewed; 168 AA. AC P51480; A2ANM1; A2ANM2; O89088; P97510; P97937; Q6PEA2; Q78E39; Q78E57; AC Q792X7; Q9QWH6; Q9QWH7; Q9QWH8; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 25-OCT-2005, sequence version 2. DT 02-SEP-2026, entry version 201. DE RecName: Full=Cyclin-dependent kinase inhibitor 2A {ECO:0000312|MGI:MGI:104738}; DE AltName: Full=Cyclin-dependent kinase 4 inhibitor A; DE Short=CDK4I; DE AltName: Full=p16-INK4a; DE Short=p16-INK4; GN Name=Cdkn2a {ECO:0000312|MGI:MGI:104738}; Synonyms=P16ink4a; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=7651726; RA Quelle D.E., Ashmun R.A., Hannon G.J., Rehberger P.A., Trono D., RA Richter K.H., Walker C., Beach D., Sherr C.J., Serrano M.; RT "Cloning and characterization of murine p16INK4a and p15INK4b genes."; RL Oncogene 11:635-645(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS PRO-18; ILE-51; RP MET-74; TYR-75 AND ARG-90. RC STRAIN=BALB/cJ, and DBA/2N; TISSUE=Spleen; RX PubMed=9482902; DOI=10.1073/pnas.95.5.2429; RA Zhang S., Ramsay E.S., Mock B.A.; RT "Cdkn2a, the cyclin-dependent kinase inhibitor encoding p16(INK4a) and RT p19(ARF), is a candidate for the plasmacytoma susceptibility locus, RT Pctr1."; RL Proc. Natl. Acad. Sci. U.S.A. 95:2429-2434(1998). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC STRAIN=129/SvJ; RA Gong Z., Li J., Fu J.; RT "Cloning and structure analysis of murine p16INK4a."; RL Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-155. RC STRAIN=C57BL/6J X DBA; RX PubMed=9178896; DOI=10.1038/sj.onc.1200969; RA Malumbres M., de Castro I.P., Santos J., Melendez B., Mangues R., RA Serrano M., Pellicer A., Fernandez-Piqueras J.; RT "Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion RT and de novo methylation with independence of p16INK4a alterations in murine RT primary T-cell lymphomas."; RL Oncogene 14:1361-1370(1997). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-155, AND VARIANTS PRO-18; ILE-51; RP GLN-90 AND SER-127. RC STRAIN=BALB/cJ, C57BL/6J, CAST/EiJ, MOLF/EiJ, and RF/J; RA Santos J., Melendez B., Perez de Castro I., Malumbres M., Serrano M., RA Pellicer A., Fernandez-Piqueras J.; RT "Comparative analysis of the p16(INK4a) and p15(INK4b) DNA sequences in RT mouse inbred strains."; RL Submitted (OCT-1996) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-42 (ISOFORM 1), AND VARIANT PRO-18. RC STRAIN=020, 129/J, A/J, A/Wy, AKR/J, B10.A, B10.D2(58N), BALB/cJ, RC C3H/21BG, C3H/HeJ, C57BL/10ScNJ, C57BL/10SN, C57BL/6By, C57BL/6J, RC C57BR/cdJ, CBA/J, DBA/2J, HS/IBG, LP/J, LS/IBG, MA/M4J, PL/J, RF/J, RC Sencar, SJL/J, SM/J, ST/J, and SWR/J; TISSUE=Lung; RX PubMed=9021155; DOI=10.1007/s003359900352; RA Herzog C.R., You M.; RT "Sequence variation and chromosomal mapping of the murine Cdkn2a tumor RT suppressor gene."; RL Mamm. Genome 8:65-66(1997). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-42, AND VARIANTS VAL-12; GLU-27 AND RP LEU-73. RX PubMed=9667743; DOI=10.1093/carcin/19.6.1045; RA Gressani K.M., Rollins L.A., Leone-Kabler S., Cline J.M., Miller M.S.; RT "Induction of mutations in Ki-ras and INK4a in liver tumors of mice exposed RT in utero to 3-methylcholanthrene."; RL Carcinogenesis 19:1045-1052(1998). RN [10] RP MUTAGENESIS OF CYS-64; ASP-76 AND 84-ASP-THR-85. RX PubMed=9012842; DOI=10.1073/pnas.94.2.669; RA Quelle D.E., Cheng M., Ashmun R.A., Sherr C.J.; RT "Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by RT p16INK4a but not by the alternative reading frame protein p19ARF."; RL Proc. Natl. Acad. Sci. U.S.A. 94:669-673(1997). CC -!- FUNCTION: Acts as a negative regulator of the proliferation of normal CC cells by interacting strongly with CDK4 and CDK6. This inhibits their CC ability to interact with cyclins D and to phosphorylate the CC retinoblastoma protein. CC -!- SUBUNIT: Heterodimer with CDK4 or CDK6. Predominamt P16 complexes CC contained CDK6. Interacts with CDK4 (both 'T-172'-phosphorylated and CC non-phosphorylated forms); the interaction inhibits cyclin D-CDK4 CC kinase activity. Interacts with ISCO2 (By similarity). {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Comment=Isoform 1 and isoform tumor suppressor ARF arise due to the CC use of two alternative first exons joined to a common exon 2 at the CC same acceptor site but in different reading frames, resulting in two CC completely different isoforms.; CC Name=1; Synonyms=p16INK4a; CC IsoId=P51480-1; Sequence=Displayed; CC Name=2; CC IsoId=P51480-2; Sequence=VSP_015867; CC Name=tumor suppressor ARF; Synonyms=p19ARF; CC IsoId=Q64364-1; Sequence=External; CC Name=smARF; CC IsoId=Q64364-2; Sequence=External; CC -!- PTM: Phosphorylation seems to increase interaction with CDK4. CC {ECO:0000250}. CC -!- POLYMORPHISM: Strain BALB/c displays a significantly reduced ability to CC inhibit phosphorylation of the retinoblastoma protein. CC -!- SIMILARITY: Belongs to the CDKN2 cyclin-dependent kinase inhibitor CC family. {ECO:0000305}. CC -!- CAUTION: The proteins described here are encoded by the gene CDKN2A, CC but are completely unrelated in terms of sequence and function to tumor CC suppressor ARF (AC Q64364) which is encoded by the same gene. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L76150; AAA85453.1; -; mRNA. DR EMBL; AF044335; AAC08962.1; -; mRNA. DR EMBL; AF044336; AAC08963.1; -; mRNA. DR EMBL; AF332190; AAK83159.1; -; Genomic_DNA. DR EMBL; AK155307; BAE33180.1; -; mRNA. DR EMBL; AL831719; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; U66087; AAB39600.1; -; Genomic_DNA. DR EMBL; U66086; AAB39600.1; JOINED; Genomic_DNA. DR EMBL; U79625; AAD00223.1; -; Genomic_DNA. DR EMBL; U79626; AAD00224.1; -; Genomic_DNA. DR EMBL; U79627; AAD00225.1; -; Genomic_DNA. DR EMBL; U79628; AAD00226.1; -; Genomic_DNA. DR EMBL; U79630; AAD00227.1; -; Genomic_DNA. DR EMBL; U79631; AAD00228.1; -; Genomic_DNA. DR EMBL; U79632; AAD00229.1; -; Genomic_DNA. DR EMBL; U49279; AAC00051.1; -; Genomic_DNA. DR EMBL; U49280; AAC00052.1; -; Genomic_DNA. DR EMBL; AF004588; AAB61416.1; -; Genomic_DNA. DR CCDS; CCDS38812.1; -. [P51480-1] DR RefSeq; NP_001035744.1; NM_001040654.1. [P51480-1] DR AlphaFoldDB; P51480; -. DR SMR; P51480; -. DR BioGRID; 198654; 46. DR DIP; DIP-60251N; -. DR IntAct; P51480; 1. DR iPTMnet; P51480; -. DR PhosphoSitePlus; P51480; -. DR PeptideAtlas; P51480; -. DR ProteomicsDB; 281299; -. [P51480-1] DR ProteomicsDB; 281300; -. [P51480-2] DR DNASU; 12578; -. DR Ensembl; ENSMUST00000060501.5; ENSMUSP00000061847.4; ENSMUSG00000044303.7. [P51480-1] DR GeneID; 12578; -. DR UCSC; uc008toh.1; mouse. [P51480-1] DR AGR; MGI:104738; -. DR CTD; 1029; -. DR MGI; MGI:104738; Cdkn2a. DR VEuPathDB; HostDB:ENSMUSG00000044303; -. DR GeneTree; ENSGT00940000163078; -. DR HOGENOM; CLU_000134_37_1_1; -. DR OMA; PNRYGRS; -. DR OrthoDB; 10410151at2759; -. DR BioGRID-ORCS; 12578; 5 hits in 77 CRISPR screens. DR Proteomes; UP000000589; Chromosome 4. DR Bgee; ENSMUSG00000044303; Expressed in yolk sac and 55 other cell types or tissues. DR ExpressionAtlas; P51480; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl. DR GO; GO:0035985; C:senescence-associated heterochromatin focus; IEA:Ensembl. DR GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; IEA:Ensembl. DR GO; GO:0051059; F:NF-kappaB binding; IEA:Ensembl. DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl. DR GO; GO:0090398; P:cellular senescence; IEA:Ensembl. DR GO; GO:0030308; P:negative regulation of cell growth; IEA:Ensembl. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0001953; P:negative regulation of cell-matrix adhesion; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:2000111; P:positive regulation of macrophage apoptotic process; IGI:BHF-UCL. DR GO; GO:0034393; P:positive regulation of smooth muscle cell apoptotic process; IGI:BHF-UCL. DR GO; GO:0007265; P:Ras protein signal transduction; IEA:Ensembl. DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IEA:Ensembl. DR GO; GO:0090399; P:replicative senescence; IEA:Ensembl. DR FunFam; 1.25.40.20:FF:000107; cyclin-dependent kinase 4 inhibitor B; 1. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR InterPro; IPR050776; Ank_Repeat/CDKN_Inhibitor. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR PANTHER; PTHR24201; ANK_REP_REGION DOMAIN-CONTAINING PROTEIN; 1. DR PANTHER; PTHR24201:SF4; CYCLIN-DEPENDENT KINASE INHIBITOR 2A; 1. DR Pfam; PF00023; Ank; 1. DR Pfam; PF12796; Ank_2; 1. DR SMART; SM00248; ANK; 4. DR SUPFAM; SSF48403; Ankyrin repeat; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. PE 1: Evidence at protein level; KW Alternative splicing; ANK repeat; Cell cycle; Cytoplasm; Nucleus; KW Phosphoprotein; Reference proteome; Repeat; Tumor suppressor. FT CHAIN 1..168 FT /note="Cyclin-dependent kinase inhibitor 2A" FT /id="PRO_0000144178" FT REPEAT 3..32 FT /note="ANK 1" FT REPEAT 36..64 FT /note="ANK 2" FT REPEAT 69..98 FT /note="ANK 3" FT REPEAT 102..131 FT /note="ANK 4" FT REGION 148..168 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 152 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P42771" FT MOD_RES 164 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P42771" FT VAR_SEQ 1..43 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_015867" FT VARIANT 12 FT /note="A -> V (in some liver tumors)" FT /evidence="ECO:0000269|PubMed:9667743" FT VARIANT 18 FT /note="H -> P (in strain: 020, BALB/c, BALB/cJ, C3H/21BG, FT C3H/HeJ, CBA/J, MA/M4J and PL/J)" FT /evidence="ECO:0000269|PubMed:9021155, FT ECO:0000269|PubMed:9482902, ECO:0000269|Ref.7" FT VARIANT 27 FT /note="G -> E (in some liver tumors)" FT /evidence="ECO:0000269|PubMed:9667743" FT VARIANT 51 FT /note="V -> I (in strain: BALB/c and BALB/cJ)" FT /evidence="ECO:0000269|PubMed:9482902, ECO:0000269|Ref.7" FT VARIANT 73 FT /note="P -> L (in some liver tumors)" FT /evidence="ECO:0000269|PubMed:9667743" FT VARIANT 74 FT /note="V -> M (in plasmacytoma cell lines)" FT /evidence="ECO:0000269|PubMed:9482902" FT VARIANT 75 FT /note="H -> Y (in plasmacytoma cell lines)" FT /evidence="ECO:0000269|PubMed:9482902" FT VARIANT 90 FT /note="H -> Q (in strain: BALB/cJ, C57BL/6J and MOLF/Ei)" FT /evidence="ECO:0000269|Ref.7" FT VARIANT 90 FT /note="H -> R (in plasmacytoma cell lines)" FT /evidence="ECO:0000269|PubMed:9482902" FT VARIANT 127 FT /note="C -> S (in strain: BALB/cJ, C57BL/6J and MOLF/Ei)" FT /evidence="ECO:0000269|Ref.7" FT MUTAGEN 64 FT /note="C->G,R: No effect on activity." FT /evidence="ECO:0000269|PubMed:9012842" FT MUTAGEN 76 FT /note="D->N: Loss of activity." FT /evidence="ECO:0000269|PubMed:9012842" FT MUTAGEN 84..85 FT /note="Missing: Loss of activity." FT /evidence="ECO:0000269|PubMed:9012842" FT CONFLICT 11 FT /note="Missing (in Ref. 1; AAA85453)" FT /evidence="ECO:0000305" SQ SEQUENCE 168 AA; 17941 MW; 9A6B0F24F34D5FEC CRC64; MESAADRLAR AAAQGRVHDV RALLEAGVSP NAPNSFGRTP IQVMMMGNVH VAALLLNYGA DSNCEDPTTF SRPVHDAARE GFLDTLVVLH GSGARLDVRD AWGRLPLDLA QERGHQDIVR YLRSAGCSLC SAGWSLCTAG NVAQTDGHSF SSSTPRALEL RGQSQEQS //