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P42771 (CD2A1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 164. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3
Alternative name(s):
Cyclin-dependent kinase 4 inhibitor A
Short name=CDK4I
Multiple tumor suppressor 1
Short name=MTS-1
p16-INK4a
Short name=p16-INK4
Short name=p16INK4A
Gene names
Name:CDKN2A
Synonyms:CDKN2, MTS1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length156 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Ref.11 Ref.13

Subunit structure

Heterodimer with CDK4 or CDK6. Predominant p16 complexes contained CDK6. Interacts (isoforms 1,2 and 4) with CDK4 (both 'T-172'-phosphorylated and non-phosphorylated forms); the interaction inhibits cyclin D-CDK4 kinase activity. Interacts with ISCO2. Ref.13 Ref.14

Subcellular location

Cytoplasm. Nucleus Ref.14.

Tissue specificity

Widely expressed but not detected in brain or skeletal muscle. Isoform 3 is pancreas-specific. Ref.2

Post-translational modification

Phosphorylation seems to increase interaction with CDK4.

Involvement in disease

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.

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.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.24 Ref.27 Ref.29 Ref.30 Ref.31 Ref.32 Ref.34 Ref.36 Ref.38 Ref.39 Ref.41 Ref.42

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.

Li-Fraumeni syndrome (LFS) [MIM:151623]: Autosomal dominant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.35

Melanoma-astrocytoma syndrome (MASTS) [MIM:155755]: Characterized by a dual predisposition to melanoma and neural system tumors, commonly astrocytoma.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.37

Sequence similarities

Belongs to the CDKN2 cyclin-dependent kinase inhibitor family.

Contains 4 ANK repeats.

Sequence caution

The sequence AAB60645.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
   Biological processCell cycle
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
Li-Fraumeni syndrome
Tumor suppressor
   DomainANK repeat
Repeat
   PTMAcetylation
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processG1/S transition of mitotic cell cycle

Inferred from direct assay PubMed 10208428. Source: BHF-UCL

Ras protein signal transduction

Inferred from expression pattern PubMed 9054499. Source: BHF-UCL

cell cycle arrest

Inferred from direct assay PubMed 15149599. Source: BHF-UCL

cell cycle checkpoint

Inferred from mutant phenotype PubMed 16243918. Source: HGNC

mitotic cell cycle

Traceable author statement. Source: Reactome

negative regulation of NF-kappaB transcription factor activity

Inferred from direct assay PubMed 10353611. Source: BHF-UCL

negative regulation of cell growth

Inferred from direct assay PubMed 10208428. Source: BHF-UCL

negative regulation of cell proliferation

Inferred from mutant phenotype PubMed 16901784. Source: UniProtKB

negative regulation of cell-matrix adhesion

Inferred from mutant phenotype PubMed 10205165. Source: BHF-UCL

negative regulation of cyclin-dependent protein serine/threonine kinase activity

Inferred from direct assay Ref.1. Source: BHF-UCL

negative regulation of phosphorylation

Inferred from direct assay PubMed 10208428Ref.1. Source: BHF-UCL

negative regulation of transcription, DNA-templated

Inferred from mutant phenotype PubMed 16901784. Source: UniProtKB

positive regulation of cellular senescence

Inferred from mutant phenotype PubMed 16901784. Source: UniProtKB

positive regulation of macrophage apoptotic process

Inferred from sequence or structural similarity PubMed 20381282. Source: BHF-UCL

positive regulation of smooth muscle cell apoptotic process

Inferred from sequence or structural similarity PubMed 20381282. Source: BHF-UCL

replicative senescence

Inferred from mutant phenotype PubMed 14720514. Source: BHF-UCL

senescence-associated heterochromatin focus assembly

Inferred from mutant phenotype PubMed 16901784. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 16243918. Source: HGNC

cytosol

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay PubMed 16243918. Source: HGNC

senescence-associated heterochromatin focus

Inferred from direct assay PubMed 16901784. Source: UniProtKB

   Molecular_functionNF-kappaB binding

Inferred from direct assay PubMed 10353611. Source: BHF-UCL

cyclin-dependent protein serine/threonine kinase inhibitor activity

Inferred from direct assay Ref.1. Source: BHF-UCL

poly(A) RNA binding

Inferred from direct assay PubMed 22681889. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 9529249. Source: BHF-UCL

protein kinase binding

Inferred from physical interaction Ref.1. Source: BHF-UCL

Complete GO annotation...

Alternative products

This entry describes 6 isoforms produced by alternative splicing. [Align] [Select]

Note: Isoform 1 and isoform 4 arise due to the use of two alternative first exons joined to a common exon 2 at the same acceptor site but in different reading frames, resulting in two completely different isoforms.
Isoform 1 (identifier: P42771-1)

Also known as: p16INK4a;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P42771-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-51: Missing.
Isoform 3 (identifier: P42771-3)

Also known as: p12;

The sequence of this isoform differs from the canonical sequence as follows:
     52-116: MMMGSARVAE...RDAWGRLPVD → GRRSAAGAGD...LGAWETKEEE
     117-156: Missing.
Isoform 4 (identifier: Q8N726-1)

Also known as: p14ARF; p19ARF; ARF;

The sequence of this isoform can be found in the external entry Q8N726.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.
Isoform 5 (identifier: P42771-4)

Also known as: p16gamma;

The sequence of this isoform differs from the canonical sequence as follows:
     153-156: DIPD → EMIGNHLWVCRSRHA
Note: Barely detectable in non-tumor cells.
Isoform 6 (identifier: Q8N726-2)

Also known as: smARF;

The sequence of this isoform can be found in the external entry Q8N726.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 156156Cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3
PRO_0000144177

Regions

Repeat11 – 4030ANK 1
Repeat44 – 7229ANK 2
Repeat77 – 10630ANK 3
Repeat110 – 13930ANK 4

Amino acid modifications

Modified residue11N-acetylmethionine Ref.15 Ref.17
Modified residue71Phosphoserine Ref.12
Modified residue81Phosphoserine Ref.12
Modified residue1401Phosphoserine Ref.12
Modified residue1521Phosphoserine Ref.12

Natural variations

Alternative sequence1 – 5151Missing in isoform 2.
VSP_015864
Alternative sequence52 – 11665MMMGS…RLPVD → GRRSAAGAGDGGRLWRTKFA GELESGSASILRKKGRLPGE FSEGVCNHRPPPGDALGAWE TKEEE in isoform 3.
VSP_015865
Alternative sequence117 – 15640Missing in isoform 3.
VSP_015866
Alternative sequence153 – 1564DIPD → EMIGNHLWVCRSRHA in isoform 5.
VSP_043577
Natural variant141D → E in a biliary tract tumor.
VAR_001408
Natural variant161L → P in a biliary tract tumor and a familial melanoma.
VAR_001409
Natural variant191A → ATA in CMM2; loss of CDK4 binding.
VAR_058549
Natural variant201A → P in a lung tumor and melanoma.
VAR_001410
Natural variant201A → S in a biliary tract tumor.
VAR_001411
Natural variant231G → D in a pancreas tumor and a melanoma; loss of CDK4 binding.
VAR_001412
Natural variant241R → C in CMM2.
VAR_001413
Natural variant241R → P in CMM2. Ref.31
VAR_001414
Natural variant241R → Q Found in a patient with multiple primary melanoma; partial loss of CDK4 binding. Ref.42
VAR_058550
Natural variant261E → D in a biliary tract tumor.
VAR_001415
Natural variant321L → P in CMM2. Ref.27
VAR_001416
Natural variant331E → D in a biliary tract tumor.
VAR_001417
Natural variant351G → A in CMM2; also found in a biliary tract tumor and a patient with uveal melanoma; partial loss of CDK4 binding. Ref.27
VAR_001418
Natural variant351G → E in CMM2. Ref.27
VAR_001419
Natural variant351G → V in CMM2; loss of CDK4 binding. Ref.42
VAR_058551
Natural variant481P → L in CMM2 and a head and neck tumor; somatic mutation. Ref.34
VAR_001420
Natural variant491I → S in a biliary tract tumor.
VAR_001421
Natural variant491I → T. Ref.24 Ref.28
VAR_001422
Natural variant501Q → R in CMM2. Ref.27
VAR_001423
Natural variant531M → I in CMM2. Ref.27 Ref.30 Ref.31
VAR_001424
Natural variant561S → I Possible polymorphism.
VAR_001425
Natural variant571A → V in pancreas carcinoma; somatic mutation; partial loss of CDK4 binding. Ref.34
VAR_001426
Natural variant581R → Q.
Corresponds to variant rs36204273 [ dbSNP | Ensembl ].
VAR_053027
Natural variant591V → G in CMM2. Ref.39
VAR_001427
Natural variant601A → T.
VAR_001428
Natural variant601A → V in melanoma; loss of CDK4 binding.
Corresponds to variant rs36204594 [ dbSNP | Ensembl ].
VAR_053028
Natural variant61 – 622EL → DV.
VAR_001429
Natural variant621L → P in CMM2.
VAR_001430
Natural variant661H → Y in non-small cell lung carcinoma. Ref.23
VAR_001431
Natural variant67 – 715Missing in melanoma; loss of CDK4 binding.
VAR_058552
Natural variant671G → R in CMM2; partial loss of CDK4 binding. Ref.42
VAR_058553
Natural variant681A → L in CMM2; requires 2 nucleotide substitutions.
VAR_001432
Natural variant681A → T in an esophagus tumor.
VAR_001433
Natural variant681A → V. Ref.30
VAR_001434
Natural variant691E → G Found in some patients with melanoma; partial loss of CDK4 binding. Ref.42
VAR_058554
Natural variant691E → K in a bladder tumor.
VAR_001435
Natural variant691E → V in a lung tumor.
VAR_001436
Natural variant711N → K in CMM2.
VAR_001437
Natural variant711N → S. Ref.24 Ref.28
VAR_001438
Natural variant721C → G in an esophagus tumor.
VAR_001439
Natural variant741D → N in a bladder tumor.
VAR_001440
Natural variant741D → V in a biliary tract tumor.
VAR_001441
Natural variant741D → Y in CMM2; loss of CDK4 binding. Ref.42
VAR_058555
Natural variant771T → P in CMM2; loss of CDK4 binding. Ref.42
VAR_058556
Natural variant801R → L in a head and neck tumor.
VAR_001442
Natural variant801R → P in CMM2; loss of CDK4 binding. Ref.42
VAR_058557
Natural variant811P → L in some patients with melanoma; impairs the function. Ref.28
Corresponds to variant rs11552823 [ dbSNP | Ensembl ].
VAR_001443
Natural variant811P → T in CMM2; loss of CDK4 binding. Ref.42
VAR_058558
Natural variant831H → N in a lung tumor.
VAR_001445
Natural variant831H → Q.
Corresponds to variant rs34968276 [ dbSNP | Ensembl ].
VAR_053029
Natural variant831H → Y in a pancreas and a head and neck tumor.
VAR_001444
Natural variant841D → E in a bladder tumor.
VAR_001446
Natural variant841D → H in non-small cell lung carcinoma. Ref.23
VAR_001447
Natural variant841D → N in an esophagus, a head and neck and a lung tumor.
VAR_001448
Natural variant841D → Y in CMM2; also found in a lung and a prostate tumor. Ref.39
Corresponds to variant rs11552822 [ dbSNP | Ensembl ].
VAR_001449
Natural variant851A → T. Ref.30
VAR_001450
Natural variant871R → P in CMM2; impairs the function. Ref.24 Ref.28
VAR_001451
Natural variant871R → W in CMM2; partial loss of CDK4 binding. Ref.39
VAR_012317
Natural variant881E → D in a biliary tract tumor.
VAR_001452
Natural variant891G → D in CMM2; somatic mutation. Ref.34
VAR_001453
Natural variant891G → S in CMM2.
VAR_001454
Natural variant931T → A in non-small cell lung carcinoma. Ref.23
VAR_001455
Natural variant941L → Q in CMM2. Ref.41
VAR_023604
Natural variant951V → A in non-small cell lung carcinoma. Ref.23
VAR_001456
Natural variant971L → R in CMM2; loss of CDK4 binding. Ref.42
VAR_001457
Natural variant981H → P in CMM2.
VAR_001458
Natural variant981H → Q in CMM2.
VAR_001459
Natural variant991R → P in CMM2; loss of CDK4 binding.
VAR_001460
Natural variant991R → Q in non-small cell lung carcinoma. Ref.23
VAR_001461
Natural variant991R → W.
Corresponds to variant rs34886500 [ dbSNP | Ensembl ].
VAR_053030
Natural variant1001A → L in CMM2; requires 2 nucleotide substitutions.
VAR_001462
Natural variant1001A → P.
VAR_001463
Natural variant1011G → W in CMM2 and FAMMMPC; impairs the function. Ref.24 Ref.28 Ref.39
VAR_001464
Natural variant1021A → E in LFS; somatic mutation. Ref.35
VAR_015818
Natural variant1021A → T.
Corresponds to variant rs35741010 [ dbSNP | Ensembl ].
VAR_053031
Natural variant104 – 1052Missing.
VAR_001465
Natural variant1071R → C in CMM2. Ref.30
VAR_001466
Natural variant1071R → H.
VAR_001467
Natural variant1081D → H in a bladder tumor.
VAR_001469
Natural variant1081D → Y in a head and neck tumor.
VAR_001468
Natural variant1121R → RR in CMM2. Ref.29
VAR_035068
Natural variant1141P → L in non-small cell lung carcinoma. Ref.23
VAR_001470
Natural variant1141P → S Found in some patients with melanoma; loss of CDK4 binding. Ref.42
VAR_058559
Natural variant1171L → M in CMM2; somatic mutation. Ref.34
VAR_001471
Natural variant1181A → T in CMM2. Ref.31
VAR_001472
Natural variant1191E → Q in a biliary tract tumor.
VAR_001473
Natural variant1201E → A in non-small cell lung carcinoma. Ref.23
VAR_001474
Natural variant1201E → K in non-small cell lung carcinoma. Ref.23
VAR_001475
Natural variant1221G → R in CMM2. Ref.38
VAR_035069
Natural variant1221G → S in a biliary tract tumor.
VAR_001476
Natural variant1231H → Q in leukemia.
Corresponds to variant rs6413463 [ dbSNP | Ensembl ].
VAR_001477
Natural variant1241R → C.
Corresponds to variant rs34170727 [ dbSNP | Ensembl ].
VAR_053032
Natural variant1241R → H in an esophagus tumor.
VAR_001478
Natural variant1261V → D in CMM2; impairs the function. Ref.24 Ref.28 Ref.36
VAR_001479
Natural variant1271A → S in squamous cell carcinoma. Ref.25
Corresponds to variant rs6413464 [ dbSNP | Ensembl ].
VAR_001480
Natural variant1321A → P in non-small cell lung carcinoma. Ref.23
VAR_001481
Natural variant1341A → V in non-small cell lung carcinoma. Ref.23
VAR_001482
Natural variant1421H → Y in non-small cell lung carcinoma. Ref.23
VAR_001483
Natural variant1441R → C in squamous cell carcinoma. Ref.25
VAR_001484
Natural variant1481A → T. Ref.24 Ref.27 Ref.28 Ref.29 Ref.30 Ref.31 Ref.34
Corresponds to variant rs3731249 [ dbSNP | Ensembl ].
VAR_001486
Natural variant1501G → V in non-small cell lung carcinoma. Ref.23
VAR_001487

Secondary structure

................................... 156
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (p16INK4a) [UniParc].

Last modified July 15, 1998. Version 2.
Checksum: E59C0E6174B48255

FASTA15616,533
        10         20         30         40         50         60 
MEPAAGSSME PSADWLATAA ARGRVEEVRA LLEAGALPNA PNSYGRRPIQ VMMMGSARVA 

        70         80         90        100        110        120 
ELLLLHGAEP NCADPATLTR PVHDAAREGF LDTLVVLHRA GARLDVRDAW GRLPVDLAEE 

       130        140        150 
LGHRDVARYL RAAAGGTRGS NHARIDAAEG PSDIPD 

« Hide

Isoform 2 [UniParc].

Checksum: 7F3FA00737E14285
Show »

FASTA10511,215
Isoform 3 (p12) [UniParc].

Checksum: F44DBC8E0EB3A7C8
Show »

FASTA11612,213
Isoform 4 (p14ARF) (p19ARF) (ARF) [UniParc].

See Q8N726.

Isoform 5 (p16gamma) [UniParc].

Checksum: 07328B24CC7ECC61
Show »

FASTA16717,883
Isoform 6 (smARF) [UniParc].

See Q8N726.

References

« Hide 'large scale' references
[1]"A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4."
Serrano M., Hannon G.J., Beach D.
Nature 366:704-707(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]"Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus."
Robertson K.D., Jones P.A.
Oncogene 18:3810-3820(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), TISSUE SPECIFICITY.
[3]"Prevalent involvement of illegitimate V(D)J recombination in chromosome 9p21 deletions in lymphoid leukemia."
Kitagawa Y., Inoue K., Sasaki S., Hayashi Y., Matsuo Y., Lieber M.R., Mizoguchi H., Yokota J., Kohno T.
J. Biol. Chem. 277:46289-46297(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]"Human p16gamma, a novel transcriptional variant of p16(INK4A), coexpresses with p16(INK4A) in cancer cells and inhibits cell-cycle progression."
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.
Oncogene 26:7017-7027(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5), ALTERNATIVE SPLICING.
[5]NIEHS SNPs program
Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]"DNA sequence and analysis of human chromosome 9."
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. expand/collapse author list , 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.
Nature 429:369-374(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]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. expand/collapse author list , 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
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]"Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence."
Hara E., Smith R., Parry D., Tahara H., Stone S., Peters G.
Mol. Cell. Biol. 16:859-867(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-20.
[9]"Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers."
Nobori T., Miura K., Wu D.J., Lois A., Takabayashi K., Carson D.A.
Nature 368:753-756(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 51-156.
[10]"A cell cycle regulator potentially involved in genesis of many tumor types."
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.
Science 264:436-440(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 51-152.
[11]"Mutations and altered expression of p16INK4 in human cancer."
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.
Proc. Natl. Acad. Sci. U.S.A. 91:11045-11049(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[12]"Phosphorylation of p16INK4A correlates with Cdk4 association."
Gump J., Stokoe D., McCormick F.
J. Biol. Chem. 278:6619-6622(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-7; SER-8; SER-140 AND SER-152.
[13]"Regulated activating Thr172 phosphorylation of cyclin-dependent kinase 4(CDK4): its relationship with cyclins and CDK 'inhibitors'."
Bockstaele L., Kooken H., Libert F., Paternot S., Dumont J.E., de Launoit Y., Roger P.P., Coulonval K.
Mol. Cell. Biol. 26:5070-5085(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CDK4, FUNCTION.
[14]"Identification and characterization of a novel protein ISOC2 that interacts with p16INK4a."
Huang X., Shi Z., Wang W., Bai J., Chen Z., Xu J., Zhang D., Fu S.
Biochem. Biophys. Res. Commun. 361:287-293(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ISOC2, SUBCELLULAR LOCATION.
[15]"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[16]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[17]"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB."
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.
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[18]"Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a."
Russo A.A., Tong L., Lee J.O., Jeffrey P.D., Pavletich N.P.
Nature 395:237-243(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF COMPLEX WITH CDK6.
[19]"Tumor suppressor INK4: comparisons of conformational properties between p16(INK4A) and p18(INK4C)."
Yuan C., Li J., Selby T.L., Byeon I.-J., Tsai M.-D.
J. Mol. Biol. 294:201-211(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR.
[20]"Tumor suppressor INK4: refinement of p16INK4A structure and determination of p15INK4B structure by comparative modeling and NMR data."
Yuan C., Selby T.L., Li J., Byeon I.J., Tsai M.D.
Protein Sci. 9:1120-1128(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR.
[21]"CDKN2 mutations in melanoma."
Dracopoli N.C., Fountain J.W.
Cancer Surv. 26:115-132(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON MELANOMA VARIANTS.
[22]"CDKN2A (p16INK4A) somatic and germline mutations."
Smith-Soerensen B., Hovig E.
Hum. Mutat. 7:294-303(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON VARIANTS.
[23]"Somatic mutations of the MTS (multiple tumor suppressor) 1/CDK4l (cyclin-dependent kinase-4 inhibitor) gene in human primary non-small cell lung carcinomas."
Hayashi N., Sugimoto Y., Tsuchiya E., Ogawa M., Nakamura Y.
Biochem. Biophys. Res. Commun. 202:1426-1430(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: 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.
[24]"Germline p16 mutations in familial melanoma."
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.
Nat. Genet. 8:15-21(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS CMM2 PRO-87; TRP-101 AND ASP-126, VARIANTS THR-49; SER-71 AND THR-148.
[25]"The MTS1 gene is frequently mutated in primary human esophageal tumors."
Zhou X., Tarmin L., Yin J., Jiang H.-Y., Suzuki H., Rhyu M.-G., Abraham J.M., Meltzer S.J.
Oncogene 9:3737-3741(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS SQUAMOUS CELL CARCINOMA SER-127 AND CYS-144.
[26]"Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer."
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.
Cancer Res. 55:1448-1451(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS.
[27]"Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds."
Walker G.J., Hussussian C.J., Flores J.F., Glendening J.M., Haluska F.G., Dracopoli N.C., Hayward N.K., Fountain J.W.
Hum. Mol. Genet. 4:1845-1852(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS CMM2 PRO-32; ALA-35; GLU-35; ARG-50 AND ILE-53, VARIANT THR-148.
[28]"Mutations associated with familial melanoma impair p16INK4 function."
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.
Nat. Genet. 10:114-116(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF VARIANTS THR-49; SER-71; LEU-81; PRO-87; TRP-101; ASP-126 AND THR-148.
[29]"Novel germline p16 mutation in familial malignant melanoma in southern Sweden."
Borg A., Johannsson U., Johannsson O., Haakansson S., Westerdahl J., Maasbaeck A., Olsson H., Ingvar C.
Cancer Res. 56:2497-2500(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CMM2 ARG-112 INS, VARIANT THR-148.
[30]"Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in familial melanoma: analysis of a clinic-based population."
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.
Proc. Natl. Acad. Sci. U.S.A. 93:8541-8545(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS CMM2 ILE-53 AND CYS-107, VARIANTS VAL-68; THR-85 AND THR-148.
[31]"Germline mutations of the CDKN2 gene in UK melanoma families."
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.
Hum. Mol. Genet. 6:2061-2067(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS CMM2 PRO-24; ILE-53 AND THR-118, VARIANT THR-148.
[32]"Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France."
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. 7:209-216(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS CMM2.
[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]"Five novel somatic CDKN2/p16 mutations identified in melanoma, glioma and carcinoma of the pancreas."
Gretarsdottir S., Olafsdottir G.H., Borg A.
Hum. Mutat. 12:212-212(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS CMM2 LEU-48; ASP-89 AND MET-117, VARIANT PANCREAS CARCINOMA VAL-57, VARIANT THR-148.
[35]"Hereditary TP53 codon 292 and somatic P16INK4A codon 94 mutations in a Li-Fraumeni syndrome family."
Gueran S., Tunca Y., Imirzalioglu N.
Cancer Genet. Cytogenet. 113:145-151(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT LFS GLU-102.
[36]"A common founder for the V126D CDKN2A mutation in seven North American melanoma-prone families."
Goldstein A.M., Liu L., Shennan M.G., Hogg D., Tucker M.A., Struewing J.P.
Br. J. Cancer 85:527-530(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CMM2 ASP-126.
[37]"A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family."
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.
Hum. Mol. Genet. 10:55-62(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN MASTS.
[38]"Germline mutation of ARF in a melanoma kindred."
Hewitt C., Lee Wu C., Evans G., Howell A., Elles R.G., Jordan R., Sloan P., Read A.P., Thakker N.
Hum. Mol. Genet. 11:1273-1279(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CMM2 ARG-122.
[39]"CDKN2A mutations in Spanish cutaneous malignant melanoma families and patients with multiple melanomas and other neoplasia."
Ruiz A., Puig S., Malvehy J., Lazaro C., Lynch M., Gimenez-Arnau A.M., Puig L., Sanchez-Conejo J., Estivill X., Castel T.
J. Med. Genet. 36:490-493(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS CMM2 GLY-59; TYR-84; TRP-87 AND TRP-101.
[40]"Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 to uveal melanoma."
Hearle N., Damato B.E., Humphreys J., Wixey J., Green H., Stone J., Easton D.F., Houlston R.S.
Invest. Ophthalmol. Vis. Sci. 44:458-462(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: POSSIBLE INVOLVEMENT IN SUSCEPTIBILITY TO UVEAL MELANOMA.
[41]"A novel L94Q mutation in the CDKN2A gene in a melanoma kindred."
Avbelj M., Hocevar M., Trebusak-Podkrajsek K., Krzisnik C., Battelino T.
Melanoma Res. 13:567-570(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CMM2 GLN-94.
[42]"Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients."
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.
Hum. Mutat. 30:564-574(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: 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, CHARACTERIZATION OF VARIANTS.
+Additional computationally mapped references.

Web resources

CDKN2A Database

Database of CDKN2A germline and somatic variants

NIEHS-SNPs
Wikipedia

P16INK4a entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L27211 mRNA. Translation: AAA92554.1.
AF115544 mRNA. Translation: AAD11437.1.
AB060808 Genomic DNA. Translation: BAB91133.1.
AF527803 Genomic DNA. Translation: AAR05391.1.
DQ318021 mRNA. Translation: ABC47036.1.
AL449423 Genomic DNA. Translation: CAH70600.1.
CH471071 Genomic DNA. Translation: EAW58599.1.
CH471071 Genomic DNA. Translation: EAW58603.1.
X94154 Genomic DNA. Translation: CAA63870.1.
AH007355 Genomic DNA. Translation: AAD14050.1.
S69804 Genomic DNA. Translation: AAD14048.1.
U12820, U12818, U12819 Genomic DNA. Translation: AAB60645.1. Different initiation.
CCDSCCDS56565.1. [P42771-4]
CCDS6510.1. [P42771-1]
PIRJE0141.
RefSeqNP_000068.1. NM_000077.4. [P42771-1]
NP_001182061.1. NM_001195132.1. [P42771-4]
NP_478104.2. NM_058197.4.
XP_005251400.1. XM_005251343.1. [P42771-2]
UniGeneHs.512599.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1A5ENMR-A1-156[»]
1BI7X-ray3.40B1-156[»]
1DC2NMR-A1-156[»]
2A5ENMR-A1-156[»]
ProteinModelPortalP42771.
SMRP42771. Positions 1-156.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107463. 133 interactions.
DIPDIP-6108N.
IntActP42771. 49 interactions.
MINTMINT-1201444.
STRING9606.ENSP00000355153.

PTM databases

PhosphoSiteP42771.

Polymorphism databases

DMDM3041660.

Proteomic databases

MaxQBP42771.
PaxDbP42771.
PRIDEP42771.

Protocols and materials databases

DNASU1029.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000304494; ENSP00000307101; ENSG00000147889. [P42771-1]
ENST00000446177; ENSP00000394932; ENSG00000147889. [P42771-4]
ENST00000494262; ENSP00000464952; ENSG00000147889. [P42771-2]
ENST00000498124; ENSP00000418915; ENSG00000147889. [P42771-4]
ENST00000498628; ENSP00000467857; ENSG00000147889. [P42771-2]
ENST00000578845; ENSP00000467390; ENSG00000147889. [P42771-2]
GeneID1029.
KEGGhsa:1029.
UCSCuc003zpk.3. human. [P42771-1]
uc010miu.3. human. [P42771-4]

Organism-specific databases

CTD1029.
GeneCardsGC09M021957.
HGNCHGNC:1787. CDKN2A.
HPACAB000093.
CAB000445.
CAB018232.
MIM151623. phenotype.
155601. phenotype.
155755. phenotype.
600160. gene.
606719. phenotype.
neXtProtNX_P42771.
Orphanet618. Familial melanoma.
1333. Familial pancreatic carcinoma.
252206. Melanoma and neural system tumor syndrome.
51013. Melanoma-pancreatic cancer syndrome.
99860. Precursor B-cell acute lymphoblastic leukemia.
99861. Precursor T-cell acute lymphoblastic leukemia.
PharmGKBPA106.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG42176.
HOGENOMHOG000290191.
HOVERGENHBG050870.
KOK06621.
OMAIGNHLWV.
OrthoDBEOG7TTQ94.
TreeFamTF352389.

Enzyme and pathway databases

ReactomeREACT_115566. Cell Cycle.
REACT_120956. Cellular responses to stress.

Gene expression databases

ArrayExpressP42771.
BgeeP42771.
CleanExHS_CDKN2A.
GenevestigatorP42771.

Family and domain databases

Gene3D1.25.40.20. 1 hit.
InterProIPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
[Graphical view]
PfamPF00023. Ank. 1 hit.
PF12796. Ank_2. 1 hit.
[Graphical view]
SMARTSM00248. ANK. 2 hits.
[Graphical view]
SUPFAMSSF48403. SSF48403. 1 hit.
PROSITEPS50297. ANK_REP_REGION. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP42771.
GeneWikiP16_(gene).
GenomeRNAi1029.
NextBio4323.
PROP42771.
SOURCESearch...

Entry information

Entry nameCD2A1_HUMAN
AccessionPrimary (citable) accession number: P42771
Secondary accession number(s): A5X2G7 expand/collapse secondary AC list , D3DRK1, O95440, Q15191, Q5VVJ5, Q96B52, Q9NP05
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: July 15, 1998
Last modified: July 9, 2014
This is version 164 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 9

Human chromosome 9: entries, gene names and cross-references to MIM