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Cyclin-dependent kinase inhibitor 2A (Cyclin-dependent kinase 4 inhibitor A) (CDK4I) (Multiple tumor suppressor 1) (MTS-1) (p16-INK4a) (p16-INK4) (p16INK4A)

 CDN2A_HUMAN             Reviewed;         156 AA.
P42771; A5X2G7; D3DRK1; O95440; Q15191; Q5VVJ5; Q96B52; Q9NP05;
01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
15-JUL-1998, sequence version 2.
25-OCT-2017, entry version 199.
RecName: Full=Cyclin-dependent kinase inhibitor 2A {ECO:0000312|HGNC:HGNC:1787};
AltName: Full=Cyclin-dependent kinase 4 inhibitor A;
Short=CDK4I;
AltName: Full=Multiple tumor suppressor 1;
Short=MTS-1;
AltName: Full=p16-INK4a;
Short=p16-INK4;
Short=p16INK4A;
Name=CDKN2A {ECO:0000312|HGNC:HGNC:1787}; Synonyms=CDKN2, MTS1;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
PubMed=8259215; DOI=10.1038/366704a0;
Serrano M., Hannon G.J., Beach D.;
"A new regulatory motif in cell-cycle control causing specific
inhibition of cyclin D/CDK4.";
Nature 366:704-707(1993).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND TISSUE SPECIFICITY.
PubMed=10445844; DOI=10.1038/sj.onc.1202737;
Robertson K.D., Jones P.A.;
"Tissue-specific alternative splicing in the human INK4a/ARF cell
cycle regulatory locus.";
Oncogene 18:3810-3820(1999).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=12228235; DOI=10.1074/jbc.M208353200;
Kitagawa Y., Inoue K., Sasaki S., Hayashi Y., Matsuo Y., Lieber M.R.,
Mizoguchi H., Yokota J., Kohno T.;
"Prevalent involvement of illegitimate V(D)J recombination in
chromosome 9p21 deletions in lymphoid leukemia.";
J. Biol. Chem. 277:46289-46297(2002).
[4]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5), AND ALTERNATIVE SPLICING.
PubMed=17486064; DOI=10.1038/sj.onc.1210507;
Lin Y.C., Diccianni M.B., Kim Y., Lin H.H., Lee C.H., Lin R.J.,
Joo S.H., Li J., Chuang T.J., Yang A.S., Kuo H.H., Tsai M.D., Yu A.L.;
"Human p16gamma, a novel transcriptional variant of p16(INK4A),
coexpresses with p16(INK4A) in cancer cells and inhibits cell-cycle
progression.";
Oncogene 26:7017-7027(2007).
[5]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
NIEHS SNPs program;
Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15164053; DOI=10.1038/nature02465;
Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
Rogers J., Dunham I.;
"DNA sequence and analysis of human chromosome 9.";
Nature 429:369-374(2004).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
[8]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-20.
PubMed=8622687; DOI=10.1128/MCB.16.3.859;
Hara E., Smith R., Parry D., Tahara H., Stone S., Peters G.;
"Regulation of p16CDKN2 expression and its implications for cell
immortalization and senescence.";
Mol. Cell. Biol. 16:859-867(1996).
[9]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 51-156.
PubMed=8152487; DOI=10.1038/368753a0;
Nobori T., Miura K., Wu D.J., Lois A., Takabayashi K., Carson D.A.;
"Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple
human cancers.";
Nature 368:753-756(1994).
[10]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 51-152.
PubMed=8153634; DOI=10.1126/science.8153634;
Kamb A., Gruis N.A., Weaver-Feldhaus J., Liu Q., Harshman K.,
Tavtigian S.V., Stockert E., Day R.S. III, Johnson B.E.,
Skolnick M.H.;
"A cell cycle regulator potentially involved in genesis of many tumor
types.";
Science 264:436-440(1994).
[11]
FUNCTION.
PubMed=7972006; DOI=10.1073/pnas.91.23.11045;
Okamoto A., Demetrick D.J., Spillare E.A., Hagiwara K., Hussain S.P.,
Bennett W.P., Forrester K., Gerwin B., Serrano M., Beach D.H.,
Harris C.C.;
"Mutations and altered expression of p16INK4 in human cancer.";
Proc. Natl. Acad. Sci. U.S.A. 91:11045-11049(1994).
[12]
PHOSPHORYLATION AT SER-7; SER-8; SER-140 AND SER-152.
PubMed=12529334; DOI=10.1074/jbc.C200622200;
Gump J., Stokoe D., McCormick F.;
"Phosphorylation of p16INK4A correlates with Cdk4 association.";
J. Biol. Chem. 278:6619-6622(2003).
[13]
INTERACTION WITH CDK4, AND FUNCTION.
PubMed=16782892; DOI=10.1128/MCB.02006-05;
Bockstaele L., Kooken H., Libert F., Paternot S., Dumont J.E.,
de Launoit Y., Roger P.P., Coulonval K.;
"Regulated activating Thr172 phosphorylation of cyclin-dependent
kinase 4(CDK4): its relationship with cyclins and CDK 'inhibitors'.";
Mol. Cell. Biol. 26:5070-5085(2006).
[14]
INTERACTION WITH ISOC2, AND SUBCELLULAR LOCATION.
PubMed=17658461; DOI=10.1016/j.bbrc.2007.06.181;
Huang X., Shi Z., Wang W., Bai J., Chen Z., Xu J., Zhang D., Fu S.;
"Identification and characterization of a novel protein ISOC2 that
interacts with p16INK4a.";
Biochem. Biophys. Res. Commun. 361:287-293(2007).
[15]
ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=19413330; DOI=10.1021/ac9004309;
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
Mohammed S.;
"Lys-N and trypsin cover complementary parts of the phosphoproteome in
a refined SCX-based approach.";
Anal. Chem. 81:4493-4501(2009).
[16]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[17]
ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=22814378; DOI=10.1073/pnas.1210303109;
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
Aldabe R.;
"N-terminal acetylome analyses and functional insights of the N-
terminal acetyltransferase NatB.";
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
[18]
X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF COMPLEX WITH CDK6.
PubMed=9751050; DOI=10.1038/26155;
Russo A.A., Tong L., Lee J.O., Jeffrey P.D., Pavletich N.P.;
"Structural basis for inhibition of the cyclin-dependent kinase Cdk6
by the tumour suppressor p16INK4a.";
Nature 395:237-243(1998).
[19]
STRUCTURE BY NMR.
PubMed=10556039; DOI=10.1006/jmbi.1999.3231;
Yuan C., Li J., Selby T.L., Byeon I.-J., Tsai M.-D.;
"Tumor suppressor INK4: comparisons of conformational properties
between p16(INK4A) and p18(INK4C).";
J. Mol. Biol. 294:201-211(1999).
[20]
STRUCTURE BY NMR.
PubMed=10892805; DOI=10.1110/ps.9.6.1120;
Yuan C., Selby T.L., Li J., Byeon I.J., Tsai M.D.;
"Tumor suppressor INK4: refinement of p16INK4A structure and
determination of p15INK4B structure by comparative modeling and NMR
data.";
Protein Sci. 9:1120-1128(2000).
[21]
REVIEW ON MELANOMA VARIANTS.
PubMed=8783570;
Dracopoli N.C., Fountain J.W.;
"CDKN2 mutations in melanoma.";
Cancer Surv. 26:115-132(1996).
[22]
REVIEW ON VARIANTS.
PubMed=8723678;
DOI=10.1002/(SICI)1098-1004(1996)7:4<294::AID-HUMU2>3.3.CO;2-I;
Smith-Soerensen B., Hovig E.;
"CDKN2A (p16INK4A) somatic and germline mutations.";
Hum. Mutat. 7:294-303(1996).
[23]
VARIANTS NON-SMALL CELL LUNG CARCINOMA TYR-66; HIS-84; ALA-93; ALA-95;
GLN-99; LEU-114; ALA-120; LYS-120; PRO-132; VAL-134; TYR-142 AND
VAL-150.
PubMed=8060323; DOI=10.1006/bbrc.1994.2090;
Hayashi N., Sugimoto Y., Tsuchiya E., Ogawa M., Nakamura Y.;
"Somatic mutations of the MTS (multiple tumor suppressor) 1/CDK4l
(cyclin-dependent kinase-4 inhibitor) gene in human primary non-small
cell lung carcinomas.";
Biochem. Biophys. Res. Commun. 202:1426-1430(1994).
[24]
VARIANTS CMM2 PRO-87; TRP-101 AND ASP-126, AND VARIANTS THR-49; SER-71
AND THR-148.
PubMed=7987387; DOI=10.1038/ng0994-15;
Hussussian C.J., Struewing J.P., Goldstein A.M., Higgins P.A.T.,
Ally D.S., Sheahan M.D., Clark W.H. Jr., Tucker M.A., Dracopoli N.C.;
"Germline p16 mutations in familial melanoma.";
Nat. Genet. 8:15-21(1994).
[25]
VARIANTS SQUAMOUS CELL CARCINOMA SER-127 AND CYS-144.
PubMed=7970734;
Zhou X., Tarmin L., Yin J., Jiang H.-Y., Suzuki H., Rhyu M.-G.,
Abraham J.M., Meltzer S.J.;
"The MTS1 gene is frequently mutated in primary human esophageal
tumors.";
Oncogene 9:3737-3741(1994).
[26]
VARIANTS.
PubMed=7882351;
Okamoto A., Hussain S.P., Hagiwara K., Spillare E.A., Rusin M.R.,
Demetrick D.J., Serrano M., Hannon G.J., Shiseki M., Zariwala M.,
Xiong Y., Beach D.H., Yokota J., Harris C.C.;
"Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in
primary and metastatic lung cancer.";
Cancer Res. 55:1448-1451(1995).
[27]
VARIANTS CMM2 PRO-32; ALA-35; GLU-35; ARG-50 AND ILE-53, AND VARIANT
THR-148.
PubMed=8595405; DOI=10.1093/hmg/4.10.1845;
Walker G.J., Hussussian C.J., Flores J.F., Glendening J.M.,
Haluska F.G., Dracopoli N.C., Hayward N.K., Fountain J.W.;
"Mutations of the CDKN2/p16INK4 gene in Australian melanoma
kindreds.";
Hum. Mol. Genet. 4:1845-1852(1995).
[28]
CHARACTERIZATION OF VARIANTS THR-49; SER-71; LEU-81; PRO-87; TRP-101;
ASP-126 AND THR-148.
PubMed=7647780; DOI=10.1038/ng0595-114;
Ranade K., Hussussian C.J., Sikorski R.S., Varmus H.E.,
Goldstein A.M., Tucker M.A., Serrano M., Hannon G.J., Beach D.,
Dracopoli N.C.;
"Mutations associated with familial melanoma impair p16INK4
function.";
Nat. Genet. 10:114-116(1995).
[29]
VARIANT CMM2 ARG-112 INS, AND VARIANT THR-148.
PubMed=8653684;
Borg A., Johannsson U., Johannsson O., Haakansson S., Westerdahl J.,
Maasbaeck A., Olsson H., Ingvar C.;
"Novel germline p16 mutation in familial malignant melanoma in
southern Sweden.";
Cancer Res. 56:2497-2500(1996).
[30]
VARIANTS CMM2 ILE-53 AND CYS-107, AND VARIANTS VAL-68; THR-85 AND
THR-148.
PubMed=8710906; DOI=10.1073/pnas.93.16.8541;
Fitzgerald M.G., Harkin D.P., Silva-Arrieta S., Macdonald D.J.,
Lucchina L.C., Unsal H., O'Neill E., Koh J., Finkelstein D.M.,
Isselbacher K.J., Sober A.J., Haber D.A.;
"Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in
familial melanoma: analysis of a clinic-based population.";
Proc. Natl. Acad. Sci. U.S.A. 93:8541-8545(1996).
[31]
VARIANTS CMM2 PRO-24; ILE-53 AND THR-118, AND VARIANT THR-148.
PubMed=9328469; DOI=10.1093/hmg/6.12.2061;
Harland M., Meloni R., Gruis N., Pinney E., Brookes S., Spurr N.K.,
Frischauf A.-M., Bataille V., Peters G., Cuzick J., Selby P.,
Bishop D.T., Bishop J.N.;
"Germline mutations of the CDKN2 gene in UK melanoma families.";
Hum. Mol. Genet. 6:2061-2067(1997).
[32]
VARIANTS CMM2.
PubMed=9425228; DOI=10.1093/hmg/7.2.209;
Soufir N., Avril M.-F., Chompret A., Demenais F., Bombled J.,
Spatz A., Stoppa-Lyonnet D., Benard J., Bressac-De Paillerets B.;
"Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone
families in France.";
Hum. Mol. Genet. 7:209-216(1998).
[33]
ERRATUM.
Soufir N., Avril M.-F., Chompret A., Demenais F., Bombled J.,
Spatz A., Stoppa-Lyonnet D., Benard J., Bressac-De Paillerets B.;
Hum. Mol. Genet. 7:941-941(1998).
[34]
VARIANTS CMM2 LEU-48; ASP-89 AND MET-117, VARIANT PANCREAS CARCINOMA
VAL-57, AND VARIANT THR-148.
PubMed=10651484;
Gretarsdottir S., Olafsdottir G.H., Borg A.;
"Five novel somatic CDKN2/p16 mutations identified in melanoma, glioma
and carcinoma of the pancreas.";
Hum. Mutat. 12:212-212(1998).
[35]
VARIANT GLU-102.
PubMed=10484981; DOI=10.1016/S0165-4608(98)00276-3;
Gueran S., Tunca Y., Imirzalioglu N.;
"Hereditary TP53 codon 292 and somatic P16INK4A codon 94 mutations in
a Li-Fraumeni syndrome family.";
Cancer Genet. Cytogenet. 113:145-151(1999).
[36]
VARIANT CMM2 ASP-126.
PubMed=11506491; DOI=10.1054/bjoc.2001.1944;
Goldstein A.M., Liu L., Shennan M.G., Hogg D., Tucker M.A.,
Struewing J.P.;
"A common founder for the V126D CDKN2A mutation in seven North
American melanoma-prone families.";
Br. J. Cancer 85:527-530(2001).
[37]
INVOLVEMENT IN MASTS.
PubMed=11136714; DOI=10.1093/hmg/10.1.55;
Randerson-Moor J.A., Harland M., Williams S., Cuthbert-Heavens D.,
Sheridan E., Aveyard J., Sibley K., Whitaker L., Knowles M.,
Bishop J.N., Bishop D.T.;
"A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural
system tumour syndrome family.";
Hum. Mol. Genet. 10:55-62(2001).
[38]
VARIANT CMM2 ARG-122.
PubMed=12019208; DOI=10.1093/hmg/11.11.1273;
Hewitt C., Lee Wu C., Evans G., Howell A., Elles R.G., Jordan R.,
Sloan P., Read A.P., Thakker N.;
"Germline mutation of ARF in a melanoma kindred.";
Hum. Mol. Genet. 11:1273-1279(2002).
[39]
VARIANTS CMM2 GLY-59; TYR-84; TRP-87 AND TRP-101.
PubMed=10874641;
Ruiz A., Puig S., Malvehy J., Lazaro C., Lynch M., Gimenez-Arnau A.M.,
Puig L., Sanchez-Conejo J., Estivill X., Castel T.;
"CDKN2A mutations in Spanish cutaneous malignant melanoma families and
patients with multiple melanomas and other neoplasia.";
J. Med. Genet. 36:490-493(1999).
[40]
POSSIBLE INVOLVEMENT IN SUSCEPTIBILITY TO UVEAL MELANOMA.
PubMed=12556369; DOI=10.1167/iovs.02-0026;
Hearle N., Damato B.E., Humphreys J., Wixey J., Green H., Stone J.,
Easton D.F., Houlston R.S.;
"Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and
P15 to uveal melanoma.";
Invest. Ophthalmol. Vis. Sci. 44:458-462(2003).
[41]
VARIANT CMM2 GLN-94.
PubMed=14646619; DOI=10.1097/00008390-200312000-00005;
Avbelj M., Hocevar M., Trebusak-Podkrajsek K., Krzisnik C.,
Battelino T.;
"A novel L94Q mutation in the CDKN2A gene in a melanoma kindred.";
Melanoma Res. 13:567-570(2003).
[42]
VARIANTS CMM2 THR-ALA-19 INS; VAL-35; ARG-67; 67-GLY--ASN-71 DEL;
TYR-74; PRO-77; PRO-80; THR-81 AND ARG-97, VARIANTS GLN-24; GLY-69 AND
SER-114, AND CHARACTERIZATION OF VARIANTS.
PubMed=19260062; DOI=10.1002/humu.20845;
Kannengiesser C., Brookes S., del Arroyo A.G., Pham D., Bombled J.,
Barrois M., Mauffret O., Avril M.F., Chompret A., Lenoir G.M.,
Sarasin A., Peters G., Bressac-de Paillerets B.;
"Functional, structural, and genetic evaluation of 20 CDKN2A germ line
mutations identified in melanoma-prone families or patients.";
Hum. Mutat. 30:564-574(2009).
-!- FUNCTION: Acts as a negative regulator of the proliferation of
normal cells by interacting strongly with CDK4 and CDK6. This
inhibits their ability to interact with cyclins D and to
phosphorylate the retinoblastoma protein.
{ECO:0000269|PubMed:16782892, ECO:0000269|PubMed:7972006}.
-!- SUBUNIT: Heterodimer with CDK4 or CDK6. Predominant p16 complexes
contained CDK6. Interacts with CDK4 (both 'T-172'-phosphorylated
and non-phosphorylated forms); the interaction inhibits cyclin D-
CDK4 kinase activity. Interacts with ISCO2.
{ECO:0000269|PubMed:16782892, ECO:0000269|PubMed:17658461}.
-!- INTERACTION:
P11802:CDK4; NbExp=13; IntAct=EBI-375053, EBI-295644;
Q00534:CDK6; NbExp=14; IntAct=EBI-375053, EBI-295663;
Q6UXH1:CRELD2; NbExp=2; IntAct=EBI-375053, EBI-3935314;
O75398:DEAF1; NbExp=2; IntAct=EBI-375053, EBI-718185;
Q00839:HNRNPU; NbExp=2; IntAct=EBI-375053, EBI-351126;
Q14566:MCM6; NbExp=4; IntAct=EBI-375053, EBI-374900;
P12004:PCNA; NbExp=8; IntAct=EBI-375053, EBI-358311;
Q8NHU6:TDRD7; NbExp=2; IntAct=EBI-375053, EBI-624505;
-!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17658461}.
Nucleus {ECO:0000269|PubMed:17658461}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=6;
Comment=Isoform 1 and isoform tumor suppressor ARF arise due to
the use of two alternative first exons joined to a common exon 2
at the same acceptor site but in different reading frames,
resulting in two completely different isoforms.;
Name=1; Synonyms=p16INK4a;
IsoId=P42771-1; Sequence=Displayed;
Name=2;
IsoId=P42771-2; Sequence=VSP_015864;
Name=3; Synonyms=p12;
IsoId=P42771-3; Sequence=VSP_015865, VSP_015866;
Name=tumor suppressor ARF; Synonyms=p14ARF, p19ARF;
IsoId=Q8N726-1; Sequence=External;
Name=5; Synonyms=p16gamma;
IsoId=P42771-4; Sequence=VSP_043577;
Note=Barely detectable in non-tumor cells.;
Name=smARF;
IsoId=Q8N726-2; Sequence=External;
-!- TISSUE SPECIFICITY: Widely expressed but not detected in brain or
skeletal muscle. Isoform 3 is pancreas-specific.
{ECO:0000269|PubMed:10445844}.
-!- PTM: Phosphorylation seems to increase interaction with CDK4.
{ECO:0000269|PubMed:12529334}.
-!- DISEASE: Note=The association between cutaneous and uveal
melanomas in some families suggests that mutations in CDKN2A may
account for a proportion of uveal melanomas. However, CDKN2A
mutations are rarely found in uveal melanoma patients.
-!- DISEASE: Melanoma, cutaneous malignant 2 (CMM2) [MIM:155601]: A
malignant neoplasm of melanocytes, arising de novo or from a pre-
existing benign nevus, which occurs most often in the skin but
also may involve other sites. {ECO:0000269|PubMed:10651484,
ECO:0000269|PubMed:10874641, ECO:0000269|PubMed:11506491,
ECO:0000269|PubMed:12019208, ECO:0000269|PubMed:14646619,
ECO:0000269|PubMed:19260062, ECO:0000269|PubMed:7987387,
ECO:0000269|PubMed:8595405, ECO:0000269|PubMed:8653684,
ECO:0000269|PubMed:8710906, ECO:0000269|PubMed:9328469,
ECO:0000269|PubMed:9425228}. Note=Disease susceptibility is
associated with variations affecting the gene represented in this
entry.
-!- DISEASE: Familial atypical multiple mole melanoma-pancreatic
carcinoma syndrome (FAMMMPC) [MIM:606719]: An inherited cancer
predisposition syndrome characterized by an increased risk of
developing malignant melanoma and/or pancreatic cancer. Mutation
carriers within families may develop either or both types of
cancer. Note=The disease is caused by mutations affecting the gene
represented in this entry.
-!- DISEASE: Melanoma-astrocytoma syndrome (MASTS) [MIM:155755]:
Characterized by a dual predisposition to melanoma and neural
system tumors, commonly astrocytoma.
{ECO:0000269|PubMed:11136714}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- SIMILARITY: Belongs to the CDKN2 cyclin-dependent kinase inhibitor
family. {ECO:0000305}.
-!- CAUTION: The proteins described here are encoded by the gene
CDKN2A, but are completely unrelated in term of sequence and
function to tumor suppressor ARF (AC Q8N726) which is encoded by
the same gene. {ECO:0000305}.
-!- SEQUENCE CAUTION:
Sequence=AAB60645.1; Type=Erroneous initiation; Evidence={ECO:0000305};
-!- WEB RESOURCE: Name=CDKN2A Database; Note=Database of CDKN2A
germline and somatic variants;
URL="https://biodesktop.uvm.edu/perl/p16";
-!- WEB RESOURCE: Name=NIEHS-SNPs;
URL="http://egp.gs.washington.edu/data/cdkn2a/";
-!- WEB RESOURCE: Name=Wikipedia; Note=P16INK4a entry;
URL="https://en.wikipedia.org/wiki/P16INK4a";
-----------------------------------------------------------------------
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EMBL; L27211; AAA92554.1; -; mRNA.
EMBL; AF115544; AAD11437.1; -; mRNA.
EMBL; AB060808; BAB91133.1; -; Genomic_DNA.
EMBL; AF527803; AAR05391.1; -; Genomic_DNA.
EMBL; DQ318021; ABC47036.1; -; mRNA.
EMBL; AL449423; CAH70600.1; -; Genomic_DNA.
EMBL; CH471071; EAW58599.1; -; Genomic_DNA.
EMBL; CH471071; EAW58603.1; -; Genomic_DNA.
EMBL; X94154; CAA63870.1; -; Genomic_DNA.
EMBL; AH007355; AAD14050.1; -; Genomic_DNA.
EMBL; S69804; AAD14048.1; -; Genomic_DNA.
EMBL; U12820; AAB60645.1; ALT_INIT; Genomic_DNA.
EMBL; U12818; AAB60645.1; JOINED; Genomic_DNA.
EMBL; U12819; AAB60645.1; JOINED; Genomic_DNA.
CCDS; CCDS56565.1; -. [P42771-4]
CCDS; CCDS6510.1; -. [P42771-1]
PIR; JE0141; JE0141.
RefSeq; NP_000068.1; NM_000077.4. [P42771-1]
RefSeq; NP_001182061.1; NM_001195132.1. [P42771-4]
RefSeq; NP_478104.2; NM_058197.4.
RefSeq; XP_005251400.1; XM_005251343.1. [P42771-2]
RefSeq; XP_011515981.1; XM_011517679.1. [P42771-2]
UniGene; Hs.512599; -.
PDB; 1A5E; NMR; -; A=1-156.
PDB; 1BI7; X-ray; 3.40 A; B=1-156.
PDB; 1DC2; NMR; -; A=1-156.
PDB; 2A5E; NMR; -; A=1-156.
PDBsum; 1A5E; -.
PDBsum; 1BI7; -.
PDBsum; 1DC2; -.
PDBsum; 2A5E; -.
ProteinModelPortal; P42771; -.
SMR; P42771; -.
BioGrid; 107463; 163.
CORUM; P42771; -.
DIP; DIP-6108N; -.
IntAct; P42771; 62.
MINT; MINT-1201444; -.
STRING; 9606.ENSP00000394932; -.
iPTMnet; P42771; -.
PhosphoSitePlus; P42771; -.
BioMuta; MTAP; -.
DMDM; 3041660; -.
EPD; P42771; -.
PaxDb; P42771; -.
PeptideAtlas; P42771; -.
PRIDE; P42771; -.
TopDownProteomics; P42771-1; -. [P42771-1]
DNASU; 1029; -.
Ensembl; ENST00000304494; ENSP00000307101; ENSG00000147889. [P42771-1]
Ensembl; ENST00000494262; ENSP00000464952; ENSG00000147889. [P42771-2]
Ensembl; ENST00000498124; ENSP00000418915; ENSG00000147889. [P42771-4]
Ensembl; ENST00000498628; ENSP00000467857; ENSG00000147889. [P42771-2]
Ensembl; ENST00000578845; ENSP00000467390; ENSG00000147889. [P42771-2]
GeneID; 1029; -.
KEGG; hsa:1029; -.
UCSC; uc003zpk.4; human. [P42771-1]
CTD; 1029; -.
DisGeNET; 1029; -.
EuPathDB; HostDB:ENSG00000147889.16; -.
GeneCards; CDKN2A; -.
HGNC; HGNC:1787; CDKN2A.
HPA; CAB000093; -.
HPA; CAB000445; -.
HPA; CAB018232; -.
MalaCards; CDKN2A; -.
MIM; 155601; phenotype.
MIM; 155755; phenotype.
MIM; 600160; gene.
MIM; 606719; phenotype.
neXtProt; NX_P42771; -.
OpenTargets; ENSG00000147889; -.
Orphanet; 404560; Familial atypical multiple mole melanoma syndrome.
Orphanet; 618; Familial melanoma.
Orphanet; 1333; Familial pancreatic carcinoma.
Orphanet; 252206; Melanoma and neural system tumor syndrome.
Orphanet; 51013; Melanoma-pancreatic cancer syndrome.
Orphanet; 99860; Precursor B-cell acute lymphoblastic leukemia.
Orphanet; 99861; Precursor T-cell acute lymphoblastic leukemia.
PharmGKB; PA106; -.
eggNOG; KOG0504; Eukaryota.
eggNOG; COG0666; LUCA.
GeneTree; ENSGT00390000004527; -.
HOGENOM; HOG000290191; -.
HOVERGEN; HBG050870; -.
InParanoid; P42771; -.
KO; K06621; -.
OMA; MMMGSSE; -.
TreeFam; TF352389; -.
Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence.
Reactome; R-HSA-2559582; Senescence-Associated Secretory Phenotype (SASP).
Reactome; R-HSA-2559585; Oncogene Induced Senescence.
Reactome; R-HSA-69231; Cyclin D associated events in G1.
SIGNOR; P42771; -.
ChiTaRS; CDKN2A; human.
EvolutionaryTrace; P42771; -.
GeneWiki; P16_(gene); -.
GenomeRNAi; 1029; -.
Proteomes; UP000005640; Chromosome 9.
Bgee; ENSG00000147889; -.
CleanEx; HS_CDKN2A; -.
ExpressionAtlas; P42771; baseline and differential.
Genevisible; P42771; HS.
GO; GO:0005737; C:cytoplasm; IDA:HGNC.
GO; GO:0005829; C:cytosol; TAS:Reactome.
GO; GO:0005634; C:nucleus; IDA:HGNC.
GO; GO:0035985; C:senescence-associated heterochromatin focus; IDA:UniProtKB.
GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; IDA:BHF-UCL.
GO; GO:0051059; F:NF-kappaB binding; IDA:BHF-UCL.
GO; GO:0019901; F:protein kinase binding; IPI:BHF-UCL.
GO; GO:0003723; F:RNA binding; IDA:UniProtKB.
GO; GO:0007050; P:cell cycle arrest; IDA:BHF-UCL.
GO; GO:0090398; P:cellular senescence; IMP:BHF-UCL.
GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IDA:BHF-UCL.
GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL.
GO; GO:0008285; P:negative regulation of cell proliferation; IDA:BHF-UCL.
GO; GO:0001953; P:negative regulation of cell-matrix adhesion; IMP:BHF-UCL.
GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; IDA:BHF-UCL.
GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:BHF-UCL.
GO; GO:0042326; P:negative regulation of phosphorylation; IDA:BHF-UCL.
GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IMP:UniProtKB.
GO; GO:2000774; P:positive regulation of cellular senescence; IMP:UniProtKB.
GO; GO:2000111; P:positive regulation of macrophage apoptotic process; ISS:BHF-UCL.
GO; GO:0034393; P:positive regulation of smooth muscle cell apoptotic process; ISS:BHF-UCL.
GO; GO:0007265; P:Ras protein signal transduction; IEP:BHF-UCL.
GO; GO:0090399; P:replicative senescence; IMP:BHF-UCL.
GO; GO:0035986; P:senescence-associated heterochromatin focus assembly; IMP:UniProtKB.
CDD; cd00204; ANK; 1.
Gene3D; 1.25.40.20; -; 2.
InterPro; IPR020683; Ankyrin_rpt-contain_dom.
InterPro; IPR036770; Ankyrin_rpt-contain_sf.
SUPFAM; SSF48403; SSF48403; 1.
PROSITE; PS50297; ANK_REP_REGION; 1.
1: Evidence at protein level;
3D-structure; Acetylation; Alternative splicing; ANK repeat;
Cell cycle; Complete proteome; Cytoplasm; Disease mutation;
Li-Fraumeni syndrome; Nucleus; Phosphoprotein; Polymorphism;
Reference proteome; Repeat; Tumor suppressor.
CHAIN 1 156 Cyclin-dependent kinase inhibitor 2A.
/FTId=PRO_0000144177.
REPEAT 11 40 ANK 1.
REPEAT 44 72 ANK 2.
REPEAT 77 106 ANK 3.
REPEAT 110 139 ANK 4.
MOD_RES 1 1 N-acetylmethionine.
{ECO:0000244|PubMed:19413330,
ECO:0000244|PubMed:22814378}.
MOD_RES 7 7 Phosphoserine.
{ECO:0000269|PubMed:12529334}.
MOD_RES 8 8 Phosphoserine.
{ECO:0000269|PubMed:12529334}.
MOD_RES 140 140 Phosphoserine.
{ECO:0000269|PubMed:12529334}.
MOD_RES 152 152 Phosphoserine.
{ECO:0000269|PubMed:12529334}.
VAR_SEQ 1 51 Missing (in isoform 2). {ECO:0000305}.
/FTId=VSP_015864.
VAR_SEQ 52 116 MMMGSARVAELLLLHGAEPNCADPATLTRPVHDAAREGFLD
TLVVLHRAGARLDVRDAWGRLPVD -> GRRSAAGAGDGGR
LWRTKFAGELESGSASILRKKGRLPGEFSEGVCNHRPPPGD
ALGAWETKEEE (in isoform 3).
{ECO:0000303|PubMed:10445844}.
/FTId=VSP_015865.
VAR_SEQ 117 156 Missing (in isoform 3).
{ECO:0000303|PubMed:10445844}.
/FTId=VSP_015866.
VAR_SEQ 153 156 DIPD -> EMIGNHLWVCRSRHA (in isoform 5).
{ECO:0000303|PubMed:17486064}.
/FTId=VSP_043577.
VARIANT 14 14 D -> E (in a biliary tract tumor).
/FTId=VAR_001408.
VARIANT 16 16 L -> P (in a biliary tract tumor and a
familial melanoma).
/FTId=VAR_001409.
VARIANT 19 19 A -> ATA (in CMM2; loss of CDK4 binding).
/FTId=VAR_058549.
VARIANT 20 20 A -> P (in a lung tumor and melanoma).
/FTId=VAR_001410.
VARIANT 20 20 A -> S (in a biliary tract tumor;
dbSNP:rs760065045).
/FTId=VAR_001411.
VARIANT 23 23 G -> D (in a pancreas tumor and a
melanoma; loss of CDK4 binding).
/FTId=VAR_001412.
VARIANT 24 24 R -> C (in CMM2).
/FTId=VAR_001413.
VARIANT 24 24 R -> P (in CMM2; dbSNP:rs104894097).
{ECO:0000269|PubMed:9328469}.
/FTId=VAR_001414.
VARIANT 24 24 R -> Q (found in a patient with multiple
primary melanoma; partial loss of CDK4
binding; dbSNP:rs104894097).
{ECO:0000269|PubMed:19260062}.
/FTId=VAR_058550.
VARIANT 26 26 E -> D (in a biliary tract tumor).
/FTId=VAR_001415.
VARIANT 32 32 L -> P (in CMM2; dbSNP:rs878853650).
{ECO:0000269|PubMed:8595405}.
/FTId=VAR_001416.
VARIANT 33 33 E -> D (in a biliary tract tumor).
/FTId=VAR_001417.
VARIANT 35 35 G -> A (in CMM2; also found in a biliary
tract tumor and a patient with uveal
melanoma; partial loss of CDK4 binding;
dbSNP:rs746834149).
{ECO:0000269|PubMed:8595405}.
/FTId=VAR_001418.
VARIANT 35 35 G -> E (in CMM2; dbSNP:rs746834149).
{ECO:0000269|PubMed:8595405}.
/FTId=VAR_001419.
VARIANT 35 35 G -> V (in CMM2; loss of CDK4 binding).
{ECO:0000269|PubMed:19260062}.
/FTId=VAR_058551.
VARIANT 48 48 P -> L (in CMM2; also found in head and
neck tumor; somatic mutation).
{ECO:0000269|PubMed:10651484}.
/FTId=VAR_001420.
VARIANT 49 49 I -> S (in a biliary tract tumor).
/FTId=VAR_001421.
VARIANT 49 49 I -> T (in dbSNP:rs199907548).
{ECO:0000269|PubMed:7647780,
ECO:0000269|PubMed:7987387}.
/FTId=VAR_001422.
VARIANT 50 50 Q -> R (in CMM2; dbSNP:rs587778189).
{ECO:0000269|PubMed:8595405}.
/FTId=VAR_001423.
VARIANT 53 53 M -> I (in CMM2; dbSNP:rs104894095).
{ECO:0000269|PubMed:8595405,
ECO:0000269|PubMed:8710906,
ECO:0000269|PubMed:9328469}.
/FTId=VAR_001424.
VARIANT 56 56 S -> I (possible polymorphism;
dbSNP:rs104894109).
/FTId=VAR_001425.
VARIANT 57 57 A -> V (in pancreas carcinoma; somatic
mutation; partial loss of CDK4 binding;
dbSNP:rs372266620).
{ECO:0000269|PubMed:10651484}.
/FTId=VAR_001426.
VARIANT 59 59 V -> G (in CMM2; dbSNP:rs104894099).
{ECO:0000269|PubMed:10874641}.
/FTId=VAR_001427.
VARIANT 60 60 A -> T (in dbSNP:rs769382085).
/FTId=VAR_001428.
VARIANT 60 60 A -> V (in melanoma; loss of CDK4
binding; dbSNP:rs36204594).
/FTId=VAR_053028.
VARIANT 61 62 EL -> DV.
/FTId=VAR_001429.
VARIANT 62 62 L -> P (in CMM2).
/FTId=VAR_001430.
VARIANT 66 66 H -> Y (in non-small cell lung
carcinoma). {ECO:0000269|PubMed:8060323}.
/FTId=VAR_001431.
VARIANT 67 71 Missing (in melanoma; loss of CDK4
binding). {ECO:0000269|PubMed:19260062}.
/FTId=VAR_058552.
VARIANT 67 67 G -> R (in CMM2; partial loss of CDK4
binding; dbSNP:rs758389471).
{ECO:0000269|PubMed:19260062}.
/FTId=VAR_058553.
VARIANT 68 68 A -> L (in CMM2; requires 2 nucleotide
substitutions; dbSNP:rs876658534).
/FTId=VAR_001432.
VARIANT 68 68 A -> T (in an esophagus tumor).
/FTId=VAR_001433.
VARIANT 68 68 A -> V. {ECO:0000269|PubMed:8710906}.
/FTId=VAR_001434.
VARIANT 69 69 E -> G (found in some patients with
melanoma; partial loss of CDK4 binding;
dbSNP:rs372670098).
{ECO:0000269|PubMed:19260062}.
/FTId=VAR_058554.
VARIANT 69 69 E -> K (in a bladder tumor).
/FTId=VAR_001435.
VARIANT 69 69 E -> V (in a lung tumor).
/FTId=VAR_001436.
VARIANT 71 71 N -> K (in CMM2).
/FTId=VAR_001437.
VARIANT 71 71 N -> S (in dbSNP:rs559848002).
{ECO:0000269|PubMed:7647780,
ECO:0000269|PubMed:7987387}.
/FTId=VAR_001438.
VARIANT 72 72 C -> G (in an esophagus tumor).
/FTId=VAR_001439.
VARIANT 74 74 D -> N (in a bladder tumor).
/FTId=VAR_001440.
VARIANT 74 74 D -> V (in a biliary tract tumor).
/FTId=VAR_001441.
VARIANT 74 74 D -> Y (in CMM2; loss of CDK4 binding;
dbSNP:rs760640852).
{ECO:0000269|PubMed:19260062}.
/FTId=VAR_058555.
VARIANT 77 77 T -> P (in CMM2; loss of CDK4 binding).
{ECO:0000269|PubMed:19260062}.
/FTId=VAR_058556.
VARIANT 80 80 R -> L (in a head and neck tumor).
/FTId=VAR_001442.
VARIANT 80 80 R -> P (in CMM2; loss of CDK4 binding).
{ECO:0000269|PubMed:19260062}.
/FTId=VAR_058557.
VARIANT 81 81 P -> L (in some patients with melanoma;
impairs the function; dbSNP:rs11552823).
{ECO:0000269|PubMed:7647780}.
/FTId=VAR_001443.
VARIANT 81 81 P -> T (in CMM2; loss of CDK4 binding).
{ECO:0000269|PubMed:19260062}.
/FTId=VAR_058558.
VARIANT 83 83 H -> N (in a lung tumor).
/FTId=VAR_001445.
VARIANT 83 83 H -> Q (in dbSNP:rs34968276).
/FTId=VAR_053029.
VARIANT 83 83 H -> Y (in a pancreas tumor; also found
in head and neck tumor;
dbSNP:rs121913385).
/FTId=VAR_001444.
VARIANT 84 84 D -> E (in a bladder tumor).
/FTId=VAR_001446.
VARIANT 84 84 D -> H (in non-small cell lung
carcinoma). {ECO:0000269|PubMed:8060323}.
/FTId=VAR_001447.
VARIANT 84 84 D -> N (in an esophagus tumor; also found
in head and neck tumor; also found in a
lung tumor; dbSNP:rs11552822).
/FTId=VAR_001448.
VARIANT 84 84 D -> Y (in CMM2; also found in a lung
tumor and a prostate tumor;
dbSNP:rs11552822).
{ECO:0000269|PubMed:10874641}.
/FTId=VAR_001449.
VARIANT 85 85 A -> T (in dbSNP:rs878853646).
{ECO:0000269|PubMed:8710906}.
/FTId=VAR_001450.
VARIANT 87 87 R -> P (in CMM2; impairs the function;
dbSNP:rs878853647).
{ECO:0000269|PubMed:7647780,
ECO:0000269|PubMed:7987387}.
/FTId=VAR_001451.
VARIANT 87 87 R -> W (in CMM2; partial loss of CDK4
binding; dbSNP:rs749714198).
{ECO:0000269|PubMed:10874641}.
/FTId=VAR_012317.
VARIANT 88 88 E -> D (in a biliary tract tumor).
/FTId=VAR_001452.
VARIANT 89 89 G -> D (in CMM2; somatic mutation;
dbSNP:rs137854599).
{ECO:0000269|PubMed:10651484}.
/FTId=VAR_001453.
VARIANT 89 89 G -> S (in CMM2; dbSNP:rs137854597).
/FTId=VAR_001454.
VARIANT 93 93 T -> A (in non-small cell lung
carcinoma). {ECO:0000269|PubMed:8060323}.
/FTId=VAR_001455.
VARIANT 94 94 L -> Q (in CMM2).
{ECO:0000269|PubMed:14646619}.
/FTId=VAR_023604.
VARIANT 95 95 V -> A (in non-small cell lung
carcinoma). {ECO:0000269|PubMed:8060323}.
/FTId=VAR_001456.
VARIANT 97 97 L -> R (in CMM2; loss of CDK4 binding).
{ECO:0000269|PubMed:19260062}.
/FTId=VAR_001457.
VARIANT 98 98 H -> P (in CMM2).
/FTId=VAR_001458.
VARIANT 98 98 H -> Q (in CMM2).
/FTId=VAR_001459.
VARIANT 99 99 R -> P (in CMM2; loss of CDK4 binding).
/FTId=VAR_001460.
VARIANT 99 99 R -> Q (in non-small cell lung carcinoma;
dbSNP:rs754806883).
{ECO:0000269|PubMed:8060323}.
/FTId=VAR_001461.
VARIANT 99 99 R -> W (in dbSNP:rs34886500).
/FTId=VAR_053030.
VARIANT 100 100 A -> L (in CMM2; requires 2 nucleotide
substitutions).
/FTId=VAR_001462.
VARIANT 100 100 A -> P.
/FTId=VAR_001463.
VARIANT 101 101 G -> W (in CMM2 and FAMMMPC; impairs the
function; dbSNP:rs104894094).
{ECO:0000269|PubMed:10874641,
ECO:0000269|PubMed:7647780,
ECO:0000269|PubMed:7987387}.
/FTId=VAR_001464.
VARIANT 102 102 A -> E (found in seminoma and
medulloblastoma tissues from Li-Fraumeni
syndrome patients carrying a mutation in
TP53; somatic mutation;
dbSNP:rs137854598).
{ECO:0000269|PubMed:10484981}.
/FTId=VAR_015818.
VARIANT 102 102 A -> T (in dbSNP:rs35741010).
/FTId=VAR_053031.
VARIANT 104 105 Missing.
/FTId=VAR_001465.
VARIANT 107 107 R -> C (in CMM2).
{ECO:0000269|PubMed:8710906}.
/FTId=VAR_001466.
VARIANT 107 107 R -> H (in dbSNP:rs370823171).
/FTId=VAR_001467.
VARIANT 108 108 D -> H (in a bladder tumor).
/FTId=VAR_001469.
VARIANT 108 108 D -> Y (in a head and neck tumor;
dbSNP:rs121913381).
/FTId=VAR_001468.
VARIANT 112 112 R -> RR (in CMM2).
{ECO:0000269|PubMed:8653684}.
/FTId=VAR_035068.
VARIANT 114 114 P -> L (in non-small cell lung carcinoma;
dbSNP:rs121913386).
{ECO:0000269|PubMed:8060323}.
/FTId=VAR_001470.
VARIANT 114 114 P -> S (found in some patients with
melanoma; loss of CDK4 binding;
dbSNP:rs104894104).
{ECO:0000269|PubMed:19260062}.
/FTId=VAR_058559.
VARIANT 117 117 L -> M (in CMM2; somatic mutation).
{ECO:0000269|PubMed:10651484}.
/FTId=VAR_001471.
VARIANT 118 118 A -> T (in CMM2).
{ECO:0000269|PubMed:9328469}.
/FTId=VAR_001472.
VARIANT 119 119 E -> Q (in a biliary tract tumor).
/FTId=VAR_001473.
VARIANT 120 120 E -> A (in non-small cell lung
carcinoma). {ECO:0000269|PubMed:8060323}.
/FTId=VAR_001474.
VARIANT 120 120 E -> K (in non-small cell lung
carcinoma). {ECO:0000269|PubMed:8060323}.
/FTId=VAR_001475.
VARIANT 122 122 G -> R (in CMM2; dbSNP:rs113798404).
{ECO:0000269|PubMed:12019208}.
/FTId=VAR_035069.
VARIANT 122 122 G -> S (in a biliary tract tumor;
dbSNP:rs113798404).
/FTId=VAR_001476.
VARIANT 123 123 H -> Q (in leukemia; dbSNP:rs6413463).
/FTId=VAR_001477.
VARIANT 124 124 R -> C (in dbSNP:rs34170727).
/FTId=VAR_053032.
VARIANT 124 124 R -> H (in an esophagus tumor;
dbSNP:rs747621669).
/FTId=VAR_001478.
VARIANT 126 126 V -> D (in CMM2; impairs the function;
dbSNP:rs104894098).
{ECO:0000269|PubMed:11506491,
ECO:0000269|PubMed:7647780,
ECO:0000269|PubMed:7987387}.
/FTId=VAR_001479.
VARIANT 127 127 A -> S (in squamous cell carcinoma;
dbSNP:rs6413464).
{ECO:0000269|PubMed:7970734}.
/FTId=VAR_001480.
VARIANT 132 132 A -> P (in non-small cell lung
carcinoma). {ECO:0000269|PubMed:8060323}.
/FTId=VAR_001481.
VARIANT 134 134 A -> V (in non-small cell lung carcinoma;
dbSNP:rs757497674).
{ECO:0000269|PubMed:8060323}.
/FTId=VAR_001482.
VARIANT 142 142 H -> Y (in non-small cell lung
carcinoma). {ECO:0000269|PubMed:8060323}.
/FTId=VAR_001483.
VARIANT 144 144 R -> C (in squamous cell carcinoma;
dbSNP:rs116150891).
{ECO:0000269|PubMed:7970734}.
/FTId=VAR_001484.
VARIANT 148 148 A -> T (in dbSNP:rs3731249).
{ECO:0000269|PubMed:10651484,
ECO:0000269|PubMed:7647780,
ECO:0000269|PubMed:7987387,
ECO:0000269|PubMed:8595405,
ECO:0000269|PubMed:8653684,
ECO:0000269|PubMed:8710906,
ECO:0000269|PubMed:9328469}.
/FTId=VAR_001486.
VARIANT 150 150 G -> V (in non-small cell lung
carcinoma). {ECO:0000269|PubMed:8060323}.
/FTId=VAR_001487.
STRAND 4 6 {ECO:0000244|PDB:2A5E}.
HELIX 15 22 {ECO:0000244|PDB:1BI7}.
HELIX 25 32 {ECO:0000244|PDB:1BI7}.
TURN 33 35 {ECO:0000244|PDB:1BI7}.
STRAND 43 45 {ECO:0000244|PDB:1BI7}.
TURN 48 50 {ECO:0000244|PDB:1BI7}.
HELIX 57 64 {ECO:0000244|PDB:1BI7}.
TURN 65 67 {ECO:0000244|PDB:1BI7}.
TURN 75 77 {ECO:0000244|PDB:1BI7}.
HELIX 81 88 {ECO:0000244|PDB:1BI7}.
HELIX 91 100 {ECO:0000244|PDB:1BI7}.
STRAND 109 111 {ECO:0000244|PDB:1A5E}.
HELIX 114 121 {ECO:0000244|PDB:1BI7}.
HELIX 124 130 {ECO:0000244|PDB:1BI7}.
TURN 133 135 {ECO:0000244|PDB:2A5E}.
TURN 141 143 {ECO:0000244|PDB:1DC2}.
STRAND 145 147 {ECO:0000244|PDB:1DC2}.
STRAND 150 153 {ECO:0000244|PDB:1A5E}.
SEQUENCE 156 AA; 16533 MW; E59C0E6174B48255 CRC64;
MEPAAGSSME PSADWLATAA ARGRVEEVRA LLEAGALPNA PNSYGRRPIQ VMMMGSARVA
ELLLLHGAEP NCADPATLTR PVHDAAREGF LDTLVVLHRA GARLDVRDAW GRLPVDLAEE
LGHRDVARYL RAAAGGTRGS NHARIDAAEG PSDIPD


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