ID CDN2A_HUMAN Reviewed; 156 AA. AC P42771; A5X2G7; D3DRK1; G3XAG3; O95440; Q15191; Q5VVJ5; Q96B52; Q9NP05; DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot. DT 15-JUL-1998, sequence version 2. DT 27-MAR-2024, entry version 242. DE RecName: Full=Cyclin-dependent kinase inhibitor 2A {ECO:0000312|HGNC:HGNC:1787}; DE AltName: Full=Cyclin-dependent kinase 4 inhibitor A; DE Short=CDK4I; DE AltName: Full=Multiple tumor suppressor 1; DE Short=MTS-1; DE AltName: Full=p16-INK4a; DE Short=p16-INK4; DE Short=p16INK4A; GN Name=CDKN2A {ECO:0000312|HGNC:HGNC:1787}; Synonyms=CDKN2, MTS1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=8259215; DOI=10.1038/366704a0; RA Serrano M., Hannon G.J., Beach D.; RT "A new regulatory motif in cell-cycle control causing specific inhibition RT of cyclin D/CDK4."; RL Nature 366:704-707(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND TISSUE SPECIFICITY. RX PubMed=10445844; DOI=10.1038/sj.onc.1202737; RA Robertson K.D., Jones P.A.; RT "Tissue-specific alternative splicing in the human INK4a/ARF cell cycle RT regulatory locus."; RL Oncogene 18:3810-3820(1999). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=12228235; DOI=10.1074/jbc.m208353200; RA Kitagawa Y., Inoue K., Sasaki S., Hayashi Y., Matsuo Y., Lieber M.R., RA Mizoguchi H., Yokota J., Kohno T.; RT "Prevalent involvement of illegitimate V(D)J recombination in chromosome RT 9p21 deletions in lymphoid leukemia."; RL J. Biol. Chem. 277:46289-46297(2002). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5), AND ALTERNATIVE SPLICING. RX PubMed=17486064; DOI=10.1038/sj.onc.1210507; RA Lin Y.C., Diccianni M.B., Kim Y., Lin H.H., Lee C.H., Lin R.J., Joo S.H., RA Li J., Chuang T.J., Yang A.S., Kuo H.H., Tsai M.D., Yu A.L.; RT "Human p16gamma, a novel transcriptional variant of p16(INK4A), coexpresses RT with p16(INK4A) in cancer cells and inhibits cell-cycle progression."; RL Oncogene 26:7017-7027(2007). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-20. RX PubMed=8622687; DOI=10.1128/mcb.16.3.859; RA Hara E., Smith R., Parry D., Tahara H., Stone S., Peters G.; RT "Regulation of p16CDKN2 expression and its implications for cell RT immortalization and senescence."; RL Mol. Cell. Biol. 16:859-867(1996). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 51-156. RX PubMed=8152487; DOI=10.1038/368753a0; RA Nobori T., Miura K., Wu D.J., Lois A., Takabayashi K., Carson D.A.; RT "Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple RT human cancers."; RL Nature 368:753-756(1994). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 51-152. RX PubMed=8153634; DOI=10.1126/science.8153634; RA Kamb A., Gruis N.A., Weaver-Feldhaus J., Liu Q., Harshman K., RA Tavtigian S.V., Stockert E., Day R.S. III, Johnson B.E., Skolnick M.H.; RT "A cell cycle regulator potentially involved in genesis of many tumor RT types."; RL Science 264:436-440(1994). RN [11] RP FUNCTION. RX PubMed=7972006; DOI=10.1073/pnas.91.23.11045; RA Okamoto A., Demetrick D.J., Spillare E.A., Hagiwara K., Hussain S.P., RA Bennett W.P., Forrester K., Gerwin B., Serrano M., Beach D.H., Harris C.C.; RT "Mutations and altered expression of p16INK4 in human cancer."; RL Proc. Natl. Acad. Sci. U.S.A. 91:11045-11049(1994). RN [12] RP PHOSPHORYLATION AT SER-7; SER-8; SER-140 AND SER-152. RX PubMed=12529334; DOI=10.1074/jbc.c200622200; RA Gump J., Stokoe D., McCormick F.; RT "Phosphorylation of p16INK4A correlates with Cdk4 association."; RL J. Biol. Chem. 278:6619-6622(2003). RN [13] RP INTERACTION WITH CDK4, AND FUNCTION. RX PubMed=16782892; DOI=10.1128/mcb.02006-05; RA Bockstaele L., Kooken H., Libert F., Paternot S., Dumont J.E., RA de Launoit Y., Roger P.P., Coulonval K.; RT "Regulated activating Thr172 phosphorylation of cyclin-dependent kinase RT 4(CDK4): its relationship with cyclins and CDK 'inhibitors'."; RL Mol. Cell. Biol. 26:5070-5085(2006). RN [14] RP INTERACTION WITH ISOC2, AND SUBCELLULAR LOCATION. RX PubMed=17658461; DOI=10.1016/j.bbrc.2007.06.181; RA Huang X., Shi Z., Wang W., Bai J., Chen Z., Xu J., Zhang D., Fu S.; RT "Identification and characterization of a novel protein ISOC2 that RT interacts with p16INK4a."; RL Biochem. Biophys. Res. Commun. 361:287-293(2007). RN [15] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [17] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [18] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF COMPLEX WITH CDK6. RX PubMed=9751050; DOI=10.1038/26155; RA Russo A.A., Tong L., Lee J.O., Jeffrey P.D., Pavletich N.P.; RT "Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the RT tumour suppressor p16INK4a."; RL Nature 395:237-243(1998). RN [19] RP STRUCTURE BY NMR. RX PubMed=10556039; DOI=10.1006/jmbi.1999.3231; RA Yuan C., Li J., Selby T.L., Byeon I.-J., Tsai M.-D.; RT "Tumor suppressor INK4: comparisons of conformational properties between RT p16(INK4A) and p18(INK4C)."; RL J. Mol. Biol. 294:201-211(1999). RN [20] RP STRUCTURE BY NMR. RX PubMed=10892805; DOI=10.1110/ps.9.6.1120; RA Yuan C., Selby T.L., Li J., Byeon I.J., Tsai M.D.; RT "Tumor suppressor INK4: refinement of p16INK4A structure and determination RT of p15INK4B structure by comparative modeling and NMR data."; RL Protein Sci. 9:1120-1128(2000). RN [21] RP REVIEW ON MELANOMA VARIANTS. RX PubMed=8783570; RA Dracopoli N.C., Fountain J.W.; RT "CDKN2 mutations in melanoma."; RL Cancer Surv. 26:115-132(1996). RN [22] RP REVIEW ON VARIANTS. RX PubMed=8723678; RX DOI=10.1002/(sici)1098-1004(1996)7:4<294::aid-humu2>3.0.co;2-9; RA Smith-Soerensen B., Hovig E.; RT "CDKN2A (p16INK4A) somatic and germline mutations."; RL Hum. Mutat. 7:294-303(1996). RN [23] RP VARIANTS NON-SMALL CELL LUNG CARCINOMA TYR-66; HIS-84; ALA-93; ALA-95; RP GLN-99; LEU-114; ALA-120; LYS-120; PRO-132; VAL-134; TYR-142 AND VAL-150. RX PubMed=8060323; DOI=10.1006/bbrc.1994.2090; RA Hayashi N., Sugimoto Y., Tsuchiya E., Ogawa M., Nakamura Y.; RT "Somatic mutations of the MTS (multiple tumor suppressor) 1/CDK4l (cyclin- RT dependent kinase-4 inhibitor) gene in human primary non-small cell lung RT carcinomas."; RL Biochem. Biophys. Res. Commun. 202:1426-1430(1994). RN [24] RP VARIANTS CMM2 PRO-87; TRP-101 AND ASP-126, AND VARIANTS THR-49; SER-71 AND RP THR-148. RX PubMed=7987387; DOI=10.1038/ng0994-15; RA Hussussian C.J., Struewing J.P., Goldstein A.M., Higgins P.A.T., Ally D.S., RA Sheahan M.D., Clark W.H. Jr., Tucker M.A., Dracopoli N.C.; RT "Germline p16 mutations in familial melanoma."; RL Nat. Genet. 8:15-21(1994). RN [25] RP VARIANTS SQUAMOUS CELL CARCINOMA SER-127 AND CYS-144. RX PubMed=7970734; RA Zhou X., Tarmin L., Yin J., Jiang H.-Y., Suzuki H., Rhyu M.-G., RA Abraham J.M., Meltzer S.J.; RT "The MTS1 gene is frequently mutated in primary human esophageal tumors."; RL Oncogene 9:3737-3741(1994). RN [26] RP VARIANTS. RX PubMed=7882351; RA Okamoto A., Hussain S.P., Hagiwara K., Spillare E.A., Rusin M.R., RA Demetrick D.J., Serrano M., Hannon G.J., Shiseki M., Zariwala M., Xiong Y., RA Beach D.H., Yokota J., Harris C.C.; RT "Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in RT primary and metastatic lung cancer."; RL Cancer Res. 55:1448-1451(1995). RN [27] RP VARIANTS CMM2 PRO-32; ALA-35; GLU-35; ARG-50 AND ILE-53, AND VARIANT RP THR-148. RX PubMed=8595405; DOI=10.1093/hmg/4.10.1845; RA Walker G.J., Hussussian C.J., Flores J.F., Glendening J.M., Haluska F.G., RA Dracopoli N.C., Hayward N.K., Fountain J.W.; RT "Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds."; RL Hum. Mol. Genet. 4:1845-1852(1995). RN [28] RP CHARACTERIZATION OF VARIANTS THR-49; SER-71; LEU-81; PRO-87; TRP-101; RP ASP-126 AND THR-148. RX PubMed=7647780; DOI=10.1038/ng0595-114; RA Ranade K., Hussussian C.J., Sikorski R.S., Varmus H.E., Goldstein A.M., RA Tucker M.A., Serrano M., Hannon G.J., Beach D., Dracopoli N.C.; RT "Mutations associated with familial melanoma impair p16INK4 function."; RL Nat. Genet. 10:114-116(1995). RN [29] RP VARIANT CMM2 ARG-112 INS, AND VARIANT THR-148. RX PubMed=8653684; RA Borg A., Johannsson U., Johannsson O., Haakansson S., Westerdahl J., RA Maasbaeck A., Olsson H., Ingvar C.; RT "Novel germline p16 mutation in familial malignant melanoma in southern RT Sweden."; RL Cancer Res. 56:2497-2500(1996). RN [30] RP VARIANTS CMM2 ILE-53 AND CYS-107, AND VARIANTS VAL-68; THR-85 AND THR-148. RX PubMed=8710906; DOI=10.1073/pnas.93.16.8541; RA Fitzgerald M.G., Harkin D.P., Silva-Arrieta S., Macdonald D.J., RA Lucchina L.C., Unsal H., O'Neill E., Koh J., Finkelstein D.M., RA Isselbacher K.J., Sober A.J., Haber D.A.; RT "Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in familial RT melanoma: analysis of a clinic-based population."; RL Proc. Natl. Acad. Sci. U.S.A. 93:8541-8545(1996). RN [31] RP VARIANTS CMM2 PRO-24; ILE-53 AND THR-118, AND VARIANT THR-148. RX PubMed=9328469; DOI=10.1093/hmg/6.12.2061; RA Harland M., Meloni R., Gruis N., Pinney E., Brookes S., Spurr N.K., RA Frischauf A.-M., Bataille V., Peters G., Cuzick J., Selby P., Bishop D.T., RA Bishop J.N.; RT "Germline mutations of the CDKN2 gene in UK melanoma families."; RL Hum. Mol. Genet. 6:2061-2067(1997). RN [32] RP VARIANTS CMM2 ILE-56; PRO-62; LEU-68; LYS-71 AND ARG-97. RX PubMed=9425228; DOI=10.1093/hmg/7.2.209; RA Soufir N., Avril M.-F., Chompret A., Demenais F., Bombled J., Spatz A., RA Stoppa-Lyonnet D., Benard J., Bressac-De Paillerets B.; RT "Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone RT families in France."; RL Hum. Mol. Genet. 7:209-216(1998). RN [33] RP ERRATUM OF PUBMED:9425228. RA Soufir N., Avril M.-F., Chompret A., Demenais F., Bombled J., Spatz A., RA Stoppa-Lyonnet D., Benard J., Bressac-De Paillerets B.; RL Hum. Mol. Genet. 7:941-941(1998). RN [34] RP VARIANTS CMM2 LEU-48; ASP-89 AND MET-117, VARIANT PANCREAS CARCINOMA RP VAL-57, AND VARIANT THR-148. RX PubMed=10651484; RA Gretarsdottir S., Olafsdottir G.H., Borg A.; RT "Five novel somatic CDKN2/p16 mutations identified in melanoma, glioma and RT carcinoma of the pancreas."; RL Hum. Mutat. 12:212-212(1998). RN [35] RP VARIANT GLU-102. RX PubMed=10484981; DOI=10.1016/s0165-4608(98)00276-3; RA Gueran S., Tunca Y., Imirzalioglu N.; RT "Hereditary TP53 codon 292 and somatic P16INK4A codon 94 mutations in a Li- RT Fraumeni syndrome family."; RL Cancer Genet. Cytogenet. 113:145-151(1999). RN [36] RP VARIANT CMM2 ASP-126. RX PubMed=11506491; DOI=10.1054/bjoc.2001.1944; RA Goldstein A.M., Liu L., Shennan M.G., Hogg D., Tucker M.A., Struewing J.P.; RT "A common founder for the V126D CDKN2A mutation in seven North American RT melanoma-prone families."; RL Br. J. Cancer 85:527-530(2001). RN [37] RP INVOLVEMENT IN MASTS. RX PubMed=11136714; DOI=10.1093/hmg/10.1.55; RA Randerson-Moor J.A., Harland M., Williams S., Cuthbert-Heavens D., RA Sheridan E., Aveyard J., Sibley K., Whitaker L., Knowles M., Bishop J.N., RA Bishop D.T.; RT "A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system RT tumour syndrome family."; RL Hum. Mol. Genet. 10:55-62(2001). RN [38] RP VARIANT CMM2 ARG-122. RX PubMed=12019208; DOI=10.1093/hmg/11.11.1273; RA Hewitt C., Lee Wu C., Evans G., Howell A., Elles R.G., Jordan R., Sloan P., RA Read A.P., Thakker N.; RT "Germline mutation of ARF in a melanoma kindred."; RL Hum. Mol. Genet. 11:1273-1279(2002). RN [39] RP VARIANTS CMM2 GLY-59; TYR-84; TRP-87 AND TRP-101. RX PubMed=10874641; RA Ruiz A., Puig S., Malvehy J., Lazaro C., Lynch M., Gimenez-Arnau A.M., RA Puig L., Sanchez-Conejo J., Estivill X., Castel T.; RT "CDKN2A mutations in Spanish cutaneous malignant melanoma families and RT patients with multiple melanomas and other neoplasia."; RL J. Med. Genet. 36:490-493(1999). RN [40] RP POSSIBLE INVOLVEMENT IN SUSCEPTIBILITY TO UVEAL MELANOMA. RX PubMed=12556369; DOI=10.1167/iovs.02-0026; RA Hearle N., Damato B.E., Humphreys J., Wixey J., Green H., Stone J., RA Easton D.F., Houlston R.S.; RT "Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 RT to uveal melanoma."; RL Invest. Ophthalmol. Vis. Sci. 44:458-462(2003). RN [41] RP VARIANT CMM2 GLN-94. RX PubMed=14646619; DOI=10.1097/01.cmr.0000056289.15046.c0; RA Avbelj M., Hocevar M., Trebusak-Podkrajsek K., Krzisnik C., Battelino T.; RT "A novel L94Q mutation in the CDKN2A gene in a melanoma kindred."; RL Melanoma Res. 13:567-570(2003). RN [42] RP VARIANTS CMM2 THR-ALA-19 INS; VAL-35; ARG-67; 67-GLY--ASN-71 DEL; TYR-74; RP PRO-77; PRO-80; THR-81 AND ARG-97, VARIANTS GLN-24; GLY-69 AND SER-114, AND RP CHARACTERIZATION OF VARIANTS. RX PubMed=19260062; DOI=10.1002/humu.20845; RA Kannengiesser C., Brookes S., del Arroyo A.G., Pham D., Bombled J., RA Barrois M., Mauffret O., Avril M.F., Chompret A., Lenoir G.M., Sarasin A., RA Peters G., Bressac-de Paillerets B.; RT "Functional, structural, and genetic evaluation of 20 CDKN2A germ line RT mutations identified in melanoma-prone families or patients."; RL Hum. Mutat. 30:564-574(2009). 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. {ECO:0000269|PubMed:16782892, CC ECO:0000269|PubMed:7972006}. CC -!- SUBUNIT: Heterodimer with CDK4 or CDK6. Predominant 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. {ECO:0000269|PubMed:16782892, CC ECO:0000269|PubMed:17658461}. CC -!- INTERACTION: CC P42771; P11802: CDK4; NbExp=16; IntAct=EBI-375053, EBI-295644; CC P42771; Q00534: CDK6; NbExp=16; IntAct=EBI-375053, EBI-295663; CC P42771; Q6UXH1: CRELD2; NbExp=2; IntAct=EBI-375053, EBI-3935314; CC P42771; O75398: DEAF1; NbExp=2; IntAct=EBI-375053, EBI-718185; CC P42771; O75496: GMNN; NbExp=2; IntAct=EBI-375053, EBI-371669; CC P42771; Q00839: HNRNPU; NbExp=2; IntAct=EBI-375053, EBI-351126; CC P42771; Q14566: MCM6; NbExp=4; IntAct=EBI-375053, EBI-374900; CC P42771; P12004: PCNA; NbExp=8; IntAct=EBI-375053, EBI-358311; CC P42771; Q8NHU6: TDRD7; NbExp=2; IntAct=EBI-375053, EBI-624505; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17658461}. Nucleus CC {ECO:0000269|PubMed:17658461}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; 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=P42771-1; Sequence=Displayed; CC Name=2; CC IsoId=P42771-2; Sequence=VSP_015864; CC Name=3; Synonyms=p12; CC IsoId=P42771-3; Sequence=VSP_015865, VSP_015866; CC Name=tumor suppressor ARF; Synonyms=p14ARF, p19ARF; CC IsoId=Q8N726-1; Sequence=External; CC Name=5; Synonyms=p16gamma; CC IsoId=P42771-4; Sequence=VSP_043577; CC Name=smARF; CC IsoId=Q8N726-2; Sequence=External; CC -!- TISSUE SPECIFICITY: Widely expressed but not detected in brain or CC skeletal muscle. Isoform 3 is pancreas-specific. CC {ECO:0000269|PubMed:10445844}. CC -!- PTM: Phosphorylation seems to increase interaction with CDK4. CC {ECO:0000269|PubMed:12529334}. CC -!- DISEASE: Note=The association between cutaneous and uveal melanomas in CC some families suggests that mutations in CDKN2A may account for a CC proportion of uveal melanomas. However, CDKN2A mutations are rarely CC found in uveal melanoma patients. CC -!- DISEASE: Melanoma, cutaneous malignant 2 (CMM2) [MIM:155601]: A CC malignant neoplasm of melanocytes, arising de novo or from a pre- CC existing benign nevus, which occurs most often in the skin but may also CC involve other sites. {ECO:0000269|PubMed:10651484, CC ECO:0000269|PubMed:10874641, ECO:0000269|PubMed:11506491, CC ECO:0000269|PubMed:12019208, ECO:0000269|PubMed:14646619, CC ECO:0000269|PubMed:19260062, ECO:0000269|PubMed:7987387, CC ECO:0000269|PubMed:8595405, ECO:0000269|PubMed:8653684, CC ECO:0000269|PubMed:8710906, ECO:0000269|PubMed:9328469, CC ECO:0000269|PubMed:9425228}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Familial atypical multiple mole melanoma-pancreatic carcinoma CC syndrome (FAMMMPC) [MIM:606719]: An inherited cancer predisposition CC syndrome characterized by an increased risk of developing malignant CC melanoma and/or pancreatic cancer. Mutation carriers within families CC may develop either or both types of cancer. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- DISEASE: Melanoma-astrocytoma syndrome (MASTS) [MIM:155755]: CC Characterized by a dual predisposition to melanoma and neural system CC tumors, commonly astrocytoma. {ECO:0000269|PubMed:11136714}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- MISCELLANEOUS: [Isoform 5]: Barely detectable in non-tumor cells. CC {ECO:0000305}. 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 Q8N726) which is encoded by the same gene. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB60645.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=CDKN2A Database; Note=Database of CDKN2A germline CC and somatic variants; CC URL="https://biodesktop.uvm.edu/perl/p16"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/cdkn2a/"; CC -!- WEB RESOURCE: Name=Wikipedia; Note=P16INK4a entry; CC URL="https://en.wikipedia.org/wiki/P16INK4a"; 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; L27211; AAA92554.1; -; mRNA. DR EMBL; AF115544; AAD11437.1; -; mRNA. DR EMBL; AB060808; BAB91133.1; -; Genomic_DNA. DR EMBL; AF527803; AAR05391.1; -; Genomic_DNA. DR EMBL; DQ318021; ABC47036.1; -; mRNA. DR EMBL; AL449423; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471071; EAW58598.1; -; Genomic_DNA. DR EMBL; CH471071; EAW58599.1; -; Genomic_DNA. DR EMBL; CH471071; EAW58603.1; -; Genomic_DNA. DR EMBL; X94154; CAA63870.1; -; Genomic_DNA. DR EMBL; AH007355; AAD14050.1; -; Genomic_DNA. DR EMBL; S69804; AAD14048.1; -; Genomic_DNA. DR EMBL; U12820; AAB60645.1; ALT_INIT; Genomic_DNA. DR EMBL; U12818; AAB60645.1; JOINED; Genomic_DNA. DR EMBL; U12819; AAB60645.1; JOINED; Genomic_DNA. DR CCDS; CCDS56565.1; -. [P42771-4] DR CCDS; CCDS6510.1; -. [P42771-1] DR CCDS; CCDS87644.1; -. [P42771-2] DR PIR; JE0141; JE0141. DR RefSeq; NP_000068.1; NM_000077.4. [P42771-1] DR RefSeq; NP_001182061.1; NM_001195132.1. [P42771-4] DR RefSeq; NP_478104.2; NM_058197.4. [P42771-3] DR RefSeq; XP_005251400.1; XM_005251343.1. DR RefSeq; XP_011515981.1; XM_011517679.1. DR PDB; 1A5E; NMR; -; A=1-156. DR PDB; 1BI7; X-ray; 3.40 A; B=1-156. DR PDB; 1DC2; NMR; -; A=1-156. DR PDB; 2A5E; NMR; -; A=1-156. DR PDB; 7OZT; X-ray; 1.74 A; BBB=1-156. DR PDBsum; 1A5E; -. DR PDBsum; 1BI7; -. DR PDBsum; 1DC2; -. DR PDBsum; 2A5E; -. DR PDBsum; 7OZT; -. DR AlphaFoldDB; P42771; -. DR BMRB; P42771; -. DR SMR; P42771; -. DR BioGRID; 107463; 329. DR CORUM; P42771; -. DR DIP; DIP-6108N; -. DR IntAct; P42771; 108. DR MINT; P42771; -. DR STRING; 9606.ENSP00000418915; -. DR ChEMBL; CHEMBL4680027; -. DR GlyGen; P42771; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P42771; -. DR PhosphoSitePlus; P42771; -. DR BioMuta; CDKN2A; -. DR DMDM; 3041660; -. DR CPTAC; CPTAC-333; -. DR CPTAC; CPTAC-334; -. DR EPD; P42771; -. DR jPOST; P42771; -. DR MassIVE; P42771; -. DR MaxQB; P42771; -. DR PaxDb; 9606-ENSP00000418915; -. DR PeptideAtlas; P42771; -. DR ProteomicsDB; 33740; -. DR ProteomicsDB; 55551; -. [P42771-1] DR ProteomicsDB; 55552; -. [P42771-2] DR ProteomicsDB; 55553; -. [P42771-3] DR ProteomicsDB; 55554; -. [P42771-4] DR Pumba; P42771; -. DR TopDownProteomics; P42771-1; -. [P42771-1] DR ABCD; P42771; 8 sequenced antibodies. DR Antibodypedia; 3608; 2027 antibodies from 55 providers. DR DNASU; 1029; -. DR Ensembl; ENST00000304494.10; ENSP00000307101.5; ENSG00000147889.18. [P42771-1] DR Ensembl; ENST00000380151.3; ENSP00000369496.3; ENSG00000147889.18. [P42771-3] DR Ensembl; ENST00000494262.5; ENSP00000464952.1; ENSG00000147889.18. [P42771-2] DR Ensembl; ENST00000498124.1; ENSP00000418915.1; ENSG00000147889.18. [P42771-4] DR Ensembl; ENST00000498628.6; ENSP00000467857.1; ENSG00000147889.18. [P42771-2] DR Ensembl; ENST00000578845.2; ENSP00000467390.1; ENSG00000147889.18. [P42771-2] DR GeneID; 1029; -. DR KEGG; hsa:1029; -. DR MANE-Select; ENST00000304494.10; ENSP00000307101.5; NM_000077.5; NP_000068.1. DR UCSC; uc003zpj.4; human. DR UCSC; uc003zpk.4; human. [P42771-1] DR AGR; HGNC:1787; -. DR CTD; 1029; -. DR DisGeNET; 1029; -. DR GeneCards; CDKN2A; -. DR HGNC; HGNC:1787; CDKN2A. DR HPA; ENSG00000147889; Tissue enhanced (choroid plexus, pituitary gland). DR MalaCards; CDKN2A; -. DR MIM; 155601; phenotype. DR MIM; 155755; phenotype. DR MIM; 600160; gene. DR MIM; 606719; phenotype. DR neXtProt; NX_P42771; -. DR OpenTargets; ENSG00000147889; -. DR Orphanet; 1501; Adrenocortical carcinoma. DR Orphanet; 585909; B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2). DR Orphanet; 404560; Familial atypical multiple mole melanoma syndrome. DR Orphanet; 618; Familial melanoma. DR Orphanet; 1333; Familial pancreatic carcinoma. DR Orphanet; 524; Li-Fraumeni syndrome. DR Orphanet; 252206; Melanoma and neural system tumor syndrome. DR Orphanet; 99861; Precursor T-cell acute lymphoblastic leukemia. DR PharmGKB; PA106; -. DR VEuPathDB; HostDB:ENSG00000147889; -. DR eggNOG; KOG0504; Eukaryota. DR GeneTree; ENSGT00940000163078; -. DR HOGENOM; CLU_2229116_0_0_1; -. DR InParanoid; P42771; -. DR OMA; PNRYGRS; -. DR OrthoDB; 2321802at2759; -. DR TreeFam; TF352389; -. DR PathwayCommons; P42771; -. DR Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence. DR Reactome; R-HSA-2559582; Senescence-Associated Secretory Phenotype (SASP). DR Reactome; R-HSA-2559585; Oncogene Induced Senescence. DR Reactome; R-HSA-69231; Cyclin D associated events in G1. DR Reactome; R-HSA-8853884; Transcriptional Regulation by VENTX. DR Reactome; R-HSA-9630791; Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4. DR Reactome; R-HSA-9630794; Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6. DR Reactome; R-HSA-9632697; Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4. DR Reactome; R-HSA-9632700; Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6. DR SignaLink; P42771; -. DR SIGNOR; P42771; -. DR BioGRID-ORCS; 1029; 29 hits in 1179 CRISPR screens. DR ChiTaRS; CDKN2A; human. DR EvolutionaryTrace; P42771; -. DR GeneWiki; P16_(gene); -. DR GenomeRNAi; 1029; -. DR Pharos; P42771; Tbio. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; P42771; Protein. DR Bgee; ENSG00000147889; Expressed in parotid gland and 174 other cell types or tissues. DR ExpressionAtlas; P42771; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:HGNC-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:HGNC-UCL. DR GO; GO:0035985; C:senescence-associated heterochromatin focus; IDA:UniProtKB. DR GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; IDA:MGI. DR GO; GO:0051059; F:NF-kappaB binding; IDA:BHF-UCL. DR GO; GO:0019901; F:protein kinase binding; IPI:BHF-UCL. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW. DR GO; GO:0090398; P:cellular senescence; IMP:BHF-UCL. DR GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:BHF-UCL. DR GO; GO:0001953; P:negative regulation of cell-matrix adhesion; IMP:BHF-UCL. DR GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; IDA:MGI. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IMP:UniProtKB. DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:BHF-UCL. DR GO; GO:0042326; P:negative regulation of phosphorylation; IDA:BHF-UCL. DR GO; GO:2000111; P:positive regulation of macrophage apoptotic process; ISS:BHF-UCL. DR GO; GO:0034393; P:positive regulation of smooth muscle cell apoptotic process; ISS:BHF-UCL. DR GO; GO:0007265; P:Ras protein signal transduction; IEP:BHF-UCL. DR GO; GO:0051726; P:regulation of cell cycle; IDA:BHF-UCL. DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IDA:BHF-UCL. DR GO; GO:0090399; P:replicative senescence; IMP:BHF-UCL. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. 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 SUPFAM; SSF48403; Ankyrin repeat; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR Genevisible; P42771; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; ANK repeat; Cell cycle; KW Cytoplasm; Disease variant; Li-Fraumeni syndrome; Nucleus; Phosphoprotein; KW Reference proteome; Repeat; Tumor suppressor. FT CHAIN 1..156 FT /note="Cyclin-dependent kinase inhibitor 2A" FT /id="PRO_0000144177" FT REPEAT 11..40 FT /note="ANK 1" FT REPEAT 44..72 FT /note="ANK 2" FT REPEAT 77..106 FT /note="ANK 3" FT REPEAT 110..139 FT /note="ANK 4" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:19413330, FT ECO:0007744|PubMed:22814378" FT MOD_RES 7 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:12529334" FT MOD_RES 8 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:12529334" FT MOD_RES 140 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:12529334" FT MOD_RES 152 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:12529334" FT VAR_SEQ 1..51 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_015864" FT VAR_SEQ 52..116 FT /note="MMMGSARVAELLLLHGAEPNCADPATLTRPVHDAAREGFLDTLVVLHRAGAR FT LDVRDAWGRLPVD -> GRGSAAGAGDGGRLWRTKFAGELESGSASILRKKGRLPGEFS FT EGVCNHRPPPGDALGAWEAKEEE (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10445844" FT /id="VSP_015865" FT VAR_SEQ 117..156 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10445844" FT /id="VSP_015866" FT VAR_SEQ 153..156 FT /note="DIPD -> EMIGNHLWVCRSRHA (in isoform 5)" FT /evidence="ECO:0000303|PubMed:17486064" FT /id="VSP_043577" FT VARIANT 14 FT /note="D -> E (in a biliary tract tumor; FT dbSNP:rs1819961127)" FT /id="VAR_001408" FT VARIANT 16 FT /note="L -> P (in a biliary tract tumor and a familial FT melanoma; dbSNP:rs864622263)" FT /id="VAR_001409" FT VARIANT 19 FT /note="A -> ATA (in CMM2; loss of CDK4 binding)" FT /id="VAR_058549" FT VARIANT 20 FT /note="A -> P (in a lung tumor and melanoma; FT dbSNP:rs760065045)" FT /id="VAR_001410" FT VARIANT 20 FT /note="A -> S (in a biliary tract tumor; FT dbSNP:rs760065045)" FT /id="VAR_001411" FT VARIANT 23 FT /note="G -> D (in a pancreas tumor and a melanoma; loss of FT CDK4 binding; dbSNP:rs1064794292)" FT /id="VAR_001412" FT VARIANT 24 FT /note="R -> P (in CMM2; dbSNP:rs104894097)" FT /evidence="ECO:0000269|PubMed:9328469" FT /id="VAR_001414" FT VARIANT 24 FT /note="R -> Q (found in a patient with multiple primary FT melanoma; partial loss of CDK4 binding; dbSNP:rs104894097)" FT /evidence="ECO:0000269|PubMed:19260062" FT /id="VAR_058550" FT VARIANT 26 FT /note="E -> D (in a biliary tract tumor)" FT /id="VAR_001415" FT VARIANT 32 FT /note="L -> P (in CMM2; dbSNP:rs878853650)" FT /evidence="ECO:0000269|PubMed:8595405" FT /id="VAR_001416" FT VARIANT 33 FT /note="E -> D (in a biliary tract tumor)" FT /id="VAR_001417" FT VARIANT 35 FT /note="G -> A (in CMM2; also found in a biliary tract tumor FT and a patient with uveal melanoma; partial loss of CDK4 FT binding; dbSNP:rs746834149)" FT /evidence="ECO:0000269|PubMed:8595405" FT /id="VAR_001418" FT VARIANT 35 FT /note="G -> E (in CMM2; dbSNP:rs746834149)" FT /evidence="ECO:0000269|PubMed:8595405" FT /id="VAR_001419" FT VARIANT 35 FT /note="G -> V (in CMM2; loss of CDK4 binding; FT dbSNP:rs746834149)" FT /evidence="ECO:0000269|PubMed:19260062" FT /id="VAR_058551" FT VARIANT 48 FT /note="P -> L (in CMM2; also found in head and neck tumor; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:10651484" FT /id="VAR_001420" FT VARIANT 49 FT /note="I -> S (in a biliary tract tumor; FT dbSNP:rs199907548)" FT /id="VAR_001421" FT VARIANT 49 FT /note="I -> T (in dbSNP:rs199907548)" FT /evidence="ECO:0000269|PubMed:7647780, FT ECO:0000269|PubMed:7987387" FT /id="VAR_001422" FT VARIANT 50 FT /note="Q -> R (in CMM2; dbSNP:rs587778189)" FT /evidence="ECO:0000269|PubMed:8595405" FT /id="VAR_001423" FT VARIANT 53 FT /note="M -> I (in CMM2; dbSNP:rs104894095)" FT /evidence="ECO:0000269|PubMed:8595405, FT ECO:0000269|PubMed:8710906, ECO:0000269|PubMed:9328469" FT /id="VAR_001424" FT VARIANT 56 FT /note="S -> I (in CMM2; dbSNP:rs104894109)" FT /evidence="ECO:0000269|PubMed:9425228" FT /id="VAR_001425" FT VARIANT 57 FT /note="A -> V (in pancreas carcinoma; somatic mutation; FT partial loss of CDK4 binding; dbSNP:rs372266620)" FT /evidence="ECO:0000269|PubMed:10651484" FT /id="VAR_001426" FT VARIANT 59 FT /note="V -> G (in CMM2; dbSNP:rs104894099)" FT /evidence="ECO:0000269|PubMed:10874641" FT /id="VAR_001427" FT VARIANT 60 FT /note="A -> T (in dbSNP:rs769382085)" FT /id="VAR_001428" FT VARIANT 60 FT /note="A -> V (in melanoma; loss of CDK4 binding; FT dbSNP:rs36204594)" FT /id="VAR_053028" FT VARIANT 61..62 FT /note="EL -> DV" FT /id="VAR_001429" FT VARIANT 62 FT /note="L -> P (in CMM2)" FT /evidence="ECO:0000269|PubMed:9425228" FT /id="VAR_001430" FT VARIANT 66 FT /note="H -> Y (in non-small cell lung carcinoma)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001431" FT VARIANT 67..71 FT /note="Missing (in melanoma; loss of CDK4 binding)" FT /evidence="ECO:0000269|PubMed:19260062" FT /id="VAR_058552" FT VARIANT 67 FT /note="G -> R (in CMM2; partial loss of CDK4 binding; FT dbSNP:rs758389471)" FT /evidence="ECO:0000269|PubMed:19260062" FT /id="VAR_058553" FT VARIANT 68 FT /note="A -> L (in CMM2; requires 2 nucleotide FT substitutions; dbSNP:rs876658534)" FT /evidence="ECO:0000269|PubMed:9425228" FT /id="VAR_001432" FT VARIANT 68 FT /note="A -> T (in an esophagus tumor)" FT /id="VAR_001433" FT VARIANT 68 FT /note="A -> V (in dbSNP:rs1060501260)" FT /evidence="ECO:0000269|PubMed:8710906" FT /id="VAR_001434" FT VARIANT 69 FT /note="E -> G (found in some patients with melanoma; FT partial loss of CDK4 binding; dbSNP:rs372670098)" FT /evidence="ECO:0000269|PubMed:19260062" FT /id="VAR_058554" FT VARIANT 69 FT /note="E -> K (in a bladder tumor)" FT /id="VAR_001435" FT VARIANT 69 FT /note="E -> V (in a lung tumor)" FT /id="VAR_001436" FT VARIANT 71 FT /note="N -> K (in CMM2)" FT /evidence="ECO:0000269|PubMed:9425228" FT /id="VAR_001437" FT VARIANT 71 FT /note="N -> S (in dbSNP:rs559848002)" FT /evidence="ECO:0000269|PubMed:7647780, FT ECO:0000269|PubMed:7987387" FT /id="VAR_001438" FT VARIANT 72 FT /note="C -> G (in an esophagus tumor)" FT /id="VAR_001439" FT VARIANT 74 FT /note="D -> N (in a bladder tumor; dbSNP:rs760640852)" FT /id="VAR_001440" FT VARIANT 74 FT /note="D -> V (in a biliary tract tumor; FT dbSNP:rs200429615)" FT /id="VAR_001441" FT VARIANT 74 FT /note="D -> Y (in CMM2; loss of CDK4 binding; FT dbSNP:rs760640852)" FT /evidence="ECO:0000269|PubMed:19260062" FT /id="VAR_058555" FT VARIANT 77 FT /note="T -> P (in CMM2; loss of CDK4 binding)" FT /evidence="ECO:0000269|PubMed:19260062" FT /id="VAR_058556" FT VARIANT 80 FT /note="R -> L (in a head and neck tumor)" FT /id="VAR_001442" FT VARIANT 80 FT /note="R -> P (in CMM2; loss of CDK4 binding; FT dbSNP:rs1057519883)" FT /evidence="ECO:0000269|PubMed:19260062" FT /id="VAR_058557" FT VARIANT 81 FT /note="P -> L (in some patients with melanoma; impairs the FT function; dbSNP:rs11552823)" FT /evidence="ECO:0000269|PubMed:7647780" FT /id="VAR_001443" FT VARIANT 81 FT /note="P -> T (in CMM2; loss of CDK4 binding; FT dbSNP:rs1334828764)" FT /evidence="ECO:0000269|PubMed:19260062" FT /id="VAR_058558" FT VARIANT 83 FT /note="H -> N (in a lung tumor)" FT /id="VAR_001445" FT VARIANT 83 FT /note="H -> Q (in dbSNP:rs34968276)" FT /id="VAR_053029" FT VARIANT 83 FT /note="H -> Y (in a pancreas tumor; also found in head and FT neck tumor; dbSNP:rs121913385)" FT /id="VAR_001444" FT VARIANT 84 FT /note="D -> E (in a bladder tumor)" FT /id="VAR_001446" FT VARIANT 84 FT /note="D -> H (in non-small cell lung carcinoma)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001447" FT VARIANT 84 FT /note="D -> N (in an esophagus tumor; also found in head FT and neck tumor; also found in a lung tumor; FT dbSNP:rs11552822)" FT /id="VAR_001448" FT VARIANT 84 FT /note="D -> Y (in CMM2; also found in a lung tumor and a FT prostate tumor; dbSNP:rs11552822)" FT /evidence="ECO:0000269|PubMed:10874641" FT /id="VAR_001449" FT VARIANT 85 FT /note="A -> T (in dbSNP:rs878853646)" FT /evidence="ECO:0000269|PubMed:8710906" FT /id="VAR_001450" FT VARIANT 87 FT /note="R -> P (in CMM2; impairs the function; FT dbSNP:rs878853647)" FT /evidence="ECO:0000269|PubMed:7647780, FT ECO:0000269|PubMed:7987387" FT /id="VAR_001451" FT VARIANT 87 FT /note="R -> W (in CMM2; partial loss of CDK4 binding; FT dbSNP:rs749714198)" FT /evidence="ECO:0000269|PubMed:10874641" FT /id="VAR_012317" FT VARIANT 88 FT /note="E -> D (in a biliary tract tumor)" FT /id="VAR_001452" FT VARIANT 89 FT /note="G -> D (in CMM2; somatic mutation; FT dbSNP:rs137854599)" FT /evidence="ECO:0000269|PubMed:10651484" FT /id="VAR_001453" FT VARIANT 89 FT /note="G -> S (in CMM2; dbSNP:rs137854597)" FT /id="VAR_001454" FT VARIANT 93 FT /note="T -> A (in non-small cell lung carcinoma)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001455" FT VARIANT 94 FT /note="L -> Q (in CMM2; dbSNP:rs1819703656)" FT /evidence="ECO:0000269|PubMed:14646619" FT /id="VAR_023604" FT VARIANT 95 FT /note="V -> A (in non-small cell lung carcinoma)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001456" FT VARIANT 97 FT /note="L -> R (in CMM2; loss of CDK4 binding)" FT /evidence="ECO:0000269|PubMed:19260062, FT ECO:0000269|PubMed:9425228" FT /id="VAR_001457" FT VARIANT 98 FT /note="H -> P (in CMM2)" FT /id="VAR_001458" FT VARIANT 98 FT /note="H -> Q (in CMM2; dbSNP:rs752685118)" FT /id="VAR_001459" FT VARIANT 99 FT /note="R -> P (in CMM2; loss of CDK4 binding; FT dbSNP:rs754806883)" FT /id="VAR_001460" FT VARIANT 99 FT /note="R -> Q (in non-small cell lung carcinoma; FT dbSNP:rs754806883)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001461" FT VARIANT 99 FT /note="R -> W (in dbSNP:rs34886500)" FT /id="VAR_053030" FT VARIANT 100 FT /note="A -> L (in CMM2; requires 2 nucleotide FT substitutions)" FT /id="VAR_001462" FT VARIANT 100 FT /note="A -> P" FT /id="VAR_001463" FT VARIANT 101 FT /note="G -> W (in CMM2 and FAMMMPC; impairs the function; FT dbSNP:rs104894094)" FT /evidence="ECO:0000269|PubMed:10874641, FT ECO:0000269|PubMed:7647780, ECO:0000269|PubMed:7987387" FT /id="VAR_001464" FT VARIANT 102 FT /note="A -> E (found in seminoma and medulloblastoma FT tissues from Li-Fraumeni syndrome patients carrying a FT mutation in TP53; somatic mutation; dbSNP:rs137854598)" FT /evidence="ECO:0000269|PubMed:10484981" FT /id="VAR_015818" FT VARIANT 102 FT /note="A -> T (in dbSNP:rs35741010)" FT /id="VAR_053031" FT VARIANT 104..105 FT /note="Missing" FT /id="VAR_001465" FT VARIANT 107 FT /note="R -> C (in CMM2; dbSNP:rs1554654024)" FT /evidence="ECO:0000269|PubMed:8710906" FT /id="VAR_001466" FT VARIANT 107 FT /note="R -> H (in dbSNP:rs370823171)" FT /id="VAR_001467" FT VARIANT 108 FT /note="D -> H (in a bladder tumor)" FT /id="VAR_001469" FT VARIANT 108 FT /note="D -> Y (in a head and neck tumor; FT dbSNP:rs121913381)" FT /id="VAR_001468" FT VARIANT 112 FT /note="R -> RR (in CMM2)" FT /evidence="ECO:0000269|PubMed:8653684" FT /id="VAR_035068" FT VARIANT 114 FT /note="P -> L (in non-small cell lung carcinoma; FT dbSNP:rs121913386)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001470" FT VARIANT 114 FT /note="P -> S (found in some patients with melanoma; loss FT of CDK4 binding; dbSNP:rs104894104)" FT /evidence="ECO:0000269|PubMed:19260062" FT /id="VAR_058559" FT VARIANT 117 FT /note="L -> M (in CMM2; somatic mutation)" FT /evidence="ECO:0000269|PubMed:10651484" FT /id="VAR_001471" FT VARIANT 118 FT /note="A -> T (in CMM2; dbSNP:rs1554653960)" FT /evidence="ECO:0000269|PubMed:9328469" FT /id="VAR_001472" FT VARIANT 119 FT /note="E -> Q (in a biliary tract tumor)" FT /id="VAR_001473" FT VARIANT 120 FT /note="E -> A (in non-small cell lung carcinoma)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001474" FT VARIANT 120 FT /note="E -> K (in non-small cell lung carcinoma)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001475" FT VARIANT 122 FT /note="G -> R (in CMM2; dbSNP:rs113798404)" FT /evidence="ECO:0000269|PubMed:12019208" FT /id="VAR_035069" FT VARIANT 122 FT /note="G -> S (in a biliary tract tumor; FT dbSNP:rs113798404)" FT /id="VAR_001476" FT VARIANT 123 FT /note="H -> Q (in leukemia; dbSNP:rs6413463)" FT /id="VAR_001477" FT VARIANT 124 FT /note="R -> C (in dbSNP:rs34170727)" FT /id="VAR_053032" FT VARIANT 124 FT /note="R -> H (in an esophagus tumor; dbSNP:rs747621669)" FT /id="VAR_001478" FT VARIANT 126 FT /note="V -> D (in CMM2; impairs the function; FT dbSNP:rs104894098)" FT /evidence="ECO:0000269|PubMed:11506491, FT ECO:0000269|PubMed:7647780, ECO:0000269|PubMed:7987387" FT /id="VAR_001479" FT VARIANT 127 FT /note="A -> S (in squamous cell carcinoma; FT dbSNP:rs6413464)" FT /evidence="ECO:0000269|PubMed:7970734" FT /id="VAR_001480" FT VARIANT 132 FT /note="A -> P (in non-small cell lung carcinoma)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001481" FT VARIANT 134 FT /note="A -> V (in non-small cell lung carcinoma; FT dbSNP:rs757497674)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001482" FT VARIANT 142 FT /note="H -> Y (in non-small cell lung carcinoma; FT dbSNP:rs1587330478)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001483" FT VARIANT 144 FT /note="R -> C (in squamous cell carcinoma; FT dbSNP:rs116150891)" FT /evidence="ECO:0000269|PubMed:7970734" FT /id="VAR_001484" FT VARIANT 148 FT /note="A -> T (in dbSNP:rs3731249)" FT /evidence="ECO:0000269|PubMed:10651484, FT ECO:0000269|PubMed:7647780, ECO:0000269|PubMed:7987387, FT ECO:0000269|PubMed:8595405, ECO:0000269|PubMed:8653684, FT ECO:0000269|PubMed:8710906, ECO:0000269|PubMed:9328469" FT /id="VAR_001486" FT VARIANT 150 FT /note="G -> V (in non-small cell lung carcinoma)" FT /evidence="ECO:0000269|PubMed:8060323" FT /id="VAR_001487" FT STRAND 4..6 FT /evidence="ECO:0007829|PDB:2A5E" FT HELIX 15..22 FT /evidence="ECO:0007829|PDB:1BI7" FT HELIX 25..32 FT /evidence="ECO:0007829|PDB:1BI7" FT TURN 33..35 FT /evidence="ECO:0007829|PDB:1BI7" FT STRAND 43..45 FT /evidence="ECO:0007829|PDB:1BI7" FT TURN 48..50 FT /evidence="ECO:0007829|PDB:1BI7" FT HELIX 57..64 FT /evidence="ECO:0007829|PDB:1BI7" FT TURN 65..67 FT /evidence="ECO:0007829|PDB:1BI7" FT TURN 75..77 FT /evidence="ECO:0007829|PDB:1BI7" FT HELIX 81..88 FT /evidence="ECO:0007829|PDB:1BI7" FT HELIX 91..100 FT /evidence="ECO:0007829|PDB:1BI7" FT STRAND 109..111 FT /evidence="ECO:0007829|PDB:1A5E" FT HELIX 114..121 FT /evidence="ECO:0007829|PDB:1BI7" FT HELIX 124..130 FT /evidence="ECO:0007829|PDB:1BI7" FT TURN 133..135 FT /evidence="ECO:0007829|PDB:2A5E" FT TURN 141..143 FT /evidence="ECO:0007829|PDB:1DC2" FT STRAND 145..147 FT /evidence="ECO:0007829|PDB:1DC2" FT STRAND 150..153 FT /evidence="ECO:0007829|PDB:1A5E" FT CONFLICT P42771-3:54 FT /note="G -> R (in Ref. 2; AAD11437)" FT /evidence="ECO:0000305" FT CONFLICT P42771-3:112 FT /note="A -> T (in Ref. 2; AAD11437)" FT /evidence="ECO:0000305" SQ SEQUENCE 156 AA; 16533 MW; E59C0E6174B48255 CRC64; MEPAAGSSME PSADWLATAA ARGRVEEVRA LLEAGALPNA PNSYGRRPIQ VMMMGSARVA ELLLLHGAEP NCADPATLTR PVHDAAREGF LDTLVVLHRA GARLDVRDAW GRLPVDLAEE LGHRDVARYL RAAAGGTRGS NHARIDAAEG PSDIPD //