CDN2A_HUMAN
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 03-AUG-2022, entry version 233.
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.
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 also may
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 ---------------------------------------------------------------------------
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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. [P42771-2]
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 PDBsum; 1A5E; -.
DR PDBsum; 1BI7; -.
DR PDBsum; 1DC2; -.
DR PDBsum; 2A5E; -.
DR AlphaFoldDB; P42771; -.
DR BMRB; P42771; -.
DR SMR; P42771; -.
DR BioGRID; 107463; 303.
DR CORUM; P42771; -.
DR DIP; DIP-6108N; -.
DR IntAct; P42771; 83.
DR MINT; P42771; -.
DR STRING; 9606.ENSP00000418915; -.
DR ChEMBL; CHEMBL4680027; -.
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; P42771; -.
DR PeptideAtlas; P42771; -.
DR PRIDE; 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 TopDownProteomics; P42771-1; -. [P42771-1]
DR ABCD; P42771; 8 sequenced antibodies.
DR Antibodypedia; 3608; 1598 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 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; 585877; B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality.
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; RDEDKGM; -.
DR OrthoDB; 1435166at2759; -.
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; 20 hits in 1089 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 173 other tissues.
DR ExpressionAtlas; P42771; baseline and differential.
DR Genevisible; P42771; HS.
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:BHF-UCL.
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:BHF-UCL.
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:0045892; P:negative regulation of transcription, DNA-templated; IMP:UniProtKB.
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:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; IBA:GO_Central.
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; -; 1.
DR InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR SUPFAM; SSF48403; SSF48403; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
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 /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 -> C (in CMM2)"
FT /id="VAR_001413"
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 dbSNP:rs104894109)"
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 /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 /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 /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)"
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 /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
