P42771 (CD2A1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	156 AA.
Sequence status	Complete.
Protein existence	Evidence 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. Cutaneous malignant melanoma 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.22 Ref.25 Ref.27 Ref.28 Ref.29 Ref.30 Ref.32 Ref.34 Ref.36 Ref.37 Ref.39 Ref.40 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.33 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.35
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 process	Cell cycle
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Li-Fraumeni syndrome Tumor suppressor
Domain	ANK repeat Repeat
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G1 phase of mitotic cell cycle Traceable author statement. Source: Reactome G1/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 induction of apoptosis Inferred from direct assay PubMed 10208428. Source: BHF-UCL 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 transcription, DNA-dependent 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_component	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_function	NF-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
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CDK4	P11802	8	EBI-375053,EBI-295644
CDK6	Q00534	9	EBI-375053,EBI-295663
CRELD2	Q6UXH1	2	EBI-375053,EBI-3935314
DEAF1	O75398	2	EBI-375053,EBI-718185
HNRNPU	Q00839	2	EBI-375053,EBI-351126
MCM6	Q14566	4	EBI-375053,EBI-374900
PCNA	P12004	8	EBI-375053,EBI-358311
TDRD7	Q8NHU6	2	EBI-375053,EBI-624505

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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 156

156

Cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3

PRO_0000144177

Regions

Repeat

11 – 40

30

ANK 1

Repeat

44 – 72

29

ANK 2

Repeat

77 – 106

30

ANK 3

Repeat

110 – 139

30

ANK 4

Amino acid modifications

Modified residue

7

1

Phosphoserine Ref.12

Modified residue

8

1

Phosphoserine Ref.12

Modified residue

140

1

Phosphoserine Ref.12

Modified residue

152

1

Phosphoserine Ref.12

Natural variations

Alternative sequence

1 – 51

51

Missing in isoform 2.

VSP_015864

Alternative sequence

52 – 116

65

MMMGS…RLPVD → GRRSAAGAGDGGRLWRTKFA GELESGSASILRKKGRLPGE FSEGVCNHRPPPGDALGAWE TKEEE in isoform 3.

VSP_015865

Alternative sequence

117 – 156

40

Missing in isoform 3.

VSP_015866

Alternative sequence

153 – 156

4

DIPD → EMIGNHLWVCRSRHA in isoform 5.

VSP_043577

Natural variant

14

1

D → E in a biliary tract tumor.

VAR_001408

Natural variant

16

1

L → P in a biliary tract tumor and a familial melanoma.

VAR_001409

Natural variant

19

1

A → ATA in CMM2; loss of CDK4 binding.

VAR_058549

Natural variant

20

1

A → P in a lung tumor and melanoma.

VAR_001410

Natural variant

20

1

A → S in a biliary tract tumor.

VAR_001411

Natural variant

23

1

G → D in a pancreas tumor and a melanoma; loss of CDK4 binding.

VAR_001412

Natural variant

24

1

R → C in CMM2.

VAR_001413

Natural variant

24

1

R → P in CMM2. Ref.29

VAR_001414

Natural variant

24

1

R → Q Found in a patient with multiple primary melanoma; partial loss of CDK4 binding. Ref.40

VAR_058550

Natural variant

26

1

E → D in a biliary tract tumor.

VAR_001415

Natural variant

32

1

L → P in CMM2. Ref.25

VAR_001416

Natural variant

33

1

E → D in a biliary tract tumor.

VAR_001417

Natural variant

35

1

G → A in CMM2; also found in a biliary tract tumor and a patient with uveal melanoma; partial loss of CDK4 binding. Ref.25

VAR_001418

Natural variant

35

1

G → E in CMM2. Ref.25

VAR_001419

Natural variant

35

1

G → V in CMM2; loss of CDK4 binding. Ref.40

VAR_058551

Natural variant

48

1

P → L in CMM2 and a head and neck tumor; somatic mutation. Ref.32

VAR_001420

Natural variant

49

1

I → S in a biliary tract tumor.

VAR_001421

Natural variant

49

1

I → T. Ref.22 Ref.26

VAR_001422

Natural variant

50

1

Q → R in CMM2. Ref.25

VAR_001423

Natural variant

53

1

M → I in CMM2. Ref.25 Ref.28 Ref.29

VAR_001424

Natural variant

56

1

S → I Possible polymorphism.

VAR_001425

Natural variant

57

1

A → V in pancreas carcinoma; somatic mutation; partial loss of CDK4 binding. Ref.32

VAR_001426

Natural variant

58

1

R → Q.
Corresponds to variant rs36204273 [ dbSNP | Ensembl ].

VAR_053027

Natural variant

59

1

V → G in CMM2. Ref.37

VAR_001427

Natural variant

60

1

A → T.

VAR_001428

Natural variant

60

1

A → V in melanoma; loss of CDK4 binding.
Corresponds to variant rs36204594 [ dbSNP | Ensembl ].

VAR_053028

Natural variant

61 – 62

2

EL → DV.

VAR_001429

Natural variant

62

1

L → P in CMM2.

VAR_001430

Natural variant

66

1

H → Y in non-small cell lung carcinoma. Ref.21

VAR_001431

Natural variant

67 – 71

5

Missing in melanoma; loss of CDK4 binding.

VAR_058552

Natural variant

67

1

G → R in CMM2; partial loss of CDK4 binding. Ref.40

VAR_058553

Natural variant

68

1

A → L in CMM2; requires 2 nucleotide substitutions.

VAR_001432

Natural variant

68

1

A → T in an esophagus tumor.

VAR_001433

Natural variant

68

1

A → V. Ref.28

VAR_001434

Natural variant

69

1

E → G Found in some patients with melanoma; partial loss of CDK4 binding. Ref.40

VAR_058554

Natural variant

69

1

E → K in a bladder tumor.

VAR_001435

Natural variant

69

1

E → V in a lung tumor.

VAR_001436

Natural variant

71

1

N → K in CMM2.

VAR_001437

Natural variant

71

1

N → S. Ref.22 Ref.26

VAR_001438

Natural variant

72

1

C → G in an esophagus tumor.

VAR_001439

Natural variant

74

1

D → N in a bladder tumor.

VAR_001440

Natural variant

74

1

D → V in a biliary tract tumor.

VAR_001441

Natural variant

74

1

D → Y in CMM2; loss of CDK4 binding. Ref.40

VAR_058555

Natural variant

77

1

T → P in CMM2; loss of CDK4 binding. Ref.40

VAR_058556

Natural variant

80

1

R → L in a head and neck tumor.

VAR_001442

Natural variant

80

1

R → P in CMM2; loss of CDK4 binding. Ref.40

VAR_058557

Natural variant

81

1

P → L in some patients with melanoma; impairs the function. Ref.26
Corresponds to variant rs11552823 [ dbSNP | Ensembl ].

VAR_001443

Natural variant

81

1

P → T in CMM2; loss of CDK4 binding. Ref.40

VAR_058558

Natural variant

83

1

H → N in a lung tumor.

VAR_001445

Natural variant

83

1

H → Q.
Corresponds to variant rs34968276 [ dbSNP | Ensembl ].

VAR_053029

Natural variant

83

1

H → Y in a pancreas and a head and neck tumor.

VAR_001444

Natural variant

84

1

D → E in a bladder tumor.

VAR_001446

Natural variant

84

1

D → H in non-small cell lung carcinoma. Ref.21

VAR_001447

Natural variant

84

1

D → N in an esophagus, a head and neck and a lung tumor.

VAR_001448

Natural variant

84

1

D → Y in CMM2; also found in a lung and a prostate tumor. Ref.37
Corresponds to variant rs11552822 [ dbSNP | Ensembl ].

VAR_001449

Natural variant

85

1

A → T. Ref.28

VAR_001450

Natural variant

87

1

R → P in CMM2; impairs the function. Ref.22 Ref.26

VAR_001451

Natural variant

87

1

R → W in CMM2; partial loss of CDK4 binding. Ref.37

VAR_012317

Natural variant

88

1

E → D in a biliary tract tumor.

VAR_001452

Natural variant

89

1

G → D in CMM2; somatic mutation. Ref.32

VAR_001453

Natural variant

89

1

G → S in CMM2.

VAR_001454

Natural variant

93

1

T → A in non-small cell lung carcinoma. Ref.21

VAR_001455

Natural variant

94

1

L → Q in CMM2. Ref.39

VAR_023604

Natural variant

95

1

V → A in non-small cell lung carcinoma. Ref.21

VAR_001456

Natural variant

97

1

L → R in CMM2; loss of CDK4 binding. Ref.40

VAR_001457

Natural variant

98

1

H → P in CMM2.

VAR_001458

Natural variant

98

1

H → Q in CMM2.

VAR_001459

Natural variant

99

1

R → P in CMM2; loss of CDK4 binding.

VAR_001460

Natural variant

99

1

R → Q in non-small cell lung carcinoma. Ref.21

VAR_001461

Natural variant

99

1

R → W.
Corresponds to variant rs34886500 [ dbSNP | Ensembl ].

VAR_053030

Natural variant

100

1

A → L in CMM2; requires 2 nucleotide substitutions.

VAR_001462

Natural variant

100

1

A → P.

VAR_001463

Natural variant

101

1

G → W in CMM2 and FAMMMPC; impairs the function. Ref.22 Ref.26 Ref.37

VAR_001464

Natural variant

102

1

A → E in LFS; somatic mutation. Ref.33

VAR_015818

Natural variant

102

1

A → T.
Corresponds to variant rs35741010 [ dbSNP | Ensembl ].

VAR_053031

Natural variant

104 – 105

2

Missing.

VAR_001465

Natural variant

107

1

R → C in CMM2. Ref.28

VAR_001466

Natural variant

107

1

R → H.

VAR_001467

Natural variant

108

1

D → H in a bladder tumor.

VAR_001469

Natural variant

108

1

D → Y in a head and neck tumor.

VAR_001468

Natural variant

112

1

R → RR in CMM2. Ref.27

VAR_035068

Natural variant

114

1

P → L in non-small cell lung carcinoma. Ref.21

VAR_001470

Natural variant

114

1

P → S Found in some patients with melanoma; loss of CDK4 binding. Ref.40

VAR_058559

Natural variant

117

1

L → M in CMM2; somatic mutation. Ref.32

VAR_001471

Natural variant

118

1

A → T in CMM2. Ref.29

VAR_001472

Natural variant

119

1

E → Q in a biliary tract tumor.

VAR_001473

Natural variant

120

1

E → A in non-small cell lung carcinoma. Ref.21

VAR_001474

Natural variant

120

1

E → K in non-small cell lung carcinoma. Ref.21

VAR_001475

Natural variant

122

1

G → R in CMM2. Ref.36

VAR_035069

Natural variant

122

1

G → S in a biliary tract tumor.

VAR_001476

Natural variant

123

1

H → Q in leukemia.
Corresponds to variant rs6413463 [ dbSNP | Ensembl ].

VAR_001477

Natural variant

124

1

R → C.
Corresponds to variant rs34170727 [ dbSNP | Ensembl ].

VAR_053032

Natural variant

124

1

R → H in an esophagus tumor.

VAR_001478

Natural variant

126

1

V → D in CMM2; impairs the function. Ref.22 Ref.26 Ref.34

VAR_001479

Natural variant

127

1

A → S in squamous cell carcinoma. Ref.23
Corresponds to variant rs6413464 [ dbSNP | Ensembl ].

VAR_001480

Natural variant

132

1

A → P in non-small cell lung carcinoma. Ref.21

VAR_001481

Natural variant

134

1

A → V in non-small cell lung carcinoma. Ref.21

VAR_001482

Natural variant

142

1

H → Y in non-small cell lung carcinoma. Ref.21

VAR_001483

Natural variant

144

1

R → C in squamous cell carcinoma. Ref.23

VAR_001484

Natural variant

148

1

A → T. Ref.22 Ref.25 Ref.26 Ref.27 Ref.28 Ref.29 Ref.32
Corresponds to variant rs3731249 [ dbSNP | Ensembl ].

VAR_001486

Natural variant

150

1

G → V in non-small cell lung carcinoma. Ref.21

VAR_001487

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

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.

.

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.

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.

.

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.

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156

Helix Strand Turn

Details...

Beta strand

4 – 6

3

Helix

15 – 22

8

Helix

25 – 32

8

Turn

33 – 35

3

Beta strand

43 – 45

3

Turn

48 – 50

3

Helix

57 – 64

8

Turn

65 – 67

3

Turn

75 – 77

3

Helix

81 – 88

8

Helix

91 – 100

10

Beta strand

109 – 111

3

Helix

114 – 121

8

Helix

124 – 130

7

Turn

133 – 135

3

Turn

141 – 143

3

Beta strand

145 – 147

3

Beta strand

150 – 153

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (p16INK4a) [UniParc]. Last modified July 15, 1998. Version 2. Checksum: E59C0E6174B48255	FASTA	156	16,533
	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
	Isoform 2 [UniParc]. Checksum: 7F3FA00737E14285	FASTA	105	11,215
	10 20 30 40 50 60 MMMGSARVAE LLLLHGAEPN CADPATLTRP VHDAAREGFL DTLVVLHRAG ARLDVRDAWG 70 80 90 100 RLPVDLAEEL GHRDVARYLR AAAGGTRGSN HARIDAAEGP SDIPD
	Isoform 3 (p12) [UniParc]. Checksum: F44DBC8E0EB3A7C8	FASTA	116	12,213
	10 20 30 40 50 60 MEPAAGSSME PSADWLATAA ARGRVEEVRA LLEAGALPNA PNSYGRRPIQ VGRRSAAGAG 70 80 90 100 110 DGGRLWRTKF AGELESGSAS ILRKKGRLPG EFSEGVCNHR PPPGDALGAW ETKEEE
	Isoform 4 (p14ARF) (p19ARF) (ARF) [UniParc]. See Q8N726.		–	–
	Isoform 5 (p16gamma) [UniParc]. Checksum: 07328B24CC7ECC61	FASTA	167	17,883
	10 20 30 40 50 60 MEPAAGSSME PSADWLATAA ARGRVEEVRA LLEAGALPNA PNSYGRRPIQ VMMMGSARVA 70 80 90 100 110 120 ELLLLHGAEP NCADPATLTR PVHDAAREGF LDTLVVLHRA GARLDVRDAW GRLPVDLAEE 130 140 150 160 LGHRDVARYL RAAAGGTRGS NHARIDAAEG PSEMIGNHLW VCRSRHA
	Isoform 6 (smARF) [UniParc]. See Q8N726.		–	–

References

	« Hide 'large scale' referencesShow '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. , 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. , 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]	"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].
[16]	"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.
[17]	"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.
[18]	"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.
[19]	"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.
[20]	"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.
[21]	"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.
[22]	"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.
[23]	"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.
[24]	"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.
[25]	"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.
[26]	"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.
[27]	"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.
[28]	"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.
[29]	"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.
[30]	"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.
[31]	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)
[32]	"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.
[33]	"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.
[34]	"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.
[35]	"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.
[36]	"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.
[37]	"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.
[38]	"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.
[39]	"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.
[40]	"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

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

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.

IPI

IPI00001560.
IPI00030733.
IPI00942408.

PIR

JE0141.

RefSeq

NP_000068.1. NM_000077.4.
NP_001182061.1. NM_001195132.1.
NP_478104.2. NM_058197.4.

UniGene

Hs.512599.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A5E	NMR	-	A	1-156	[»]
1BI7	X-ray	3.40	B	1-156	[»]
1DC2	NMR	-	A	1-156	[»]
2A5E	NMR	-	A	1-156	[»]

ProteinModelPortal

P42771.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-6108N.

IntAct

P42771. 49 interactions.

MINT

MINT-1201444.

STRING

9606.ENSP00000355153.

PTM databases

PhosphoSite

P42771.

Polymorphism databases

DMDM

3041660.

Proteomic databases

PaxDb

P42771.

PRIDE

P42771.

Protocols and materials databases

DNASU

1029.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000304494; ENSP00000307101; ENSG00000147889.
ENST00000446177; ENSP00000394932; ENSG00000147889.
ENST00000494262; ENSP00000464952; ENSG00000147889.
ENST00000498124; ENSP00000418915; ENSG00000147889.
ENST00000498628; ENSP00000467857; ENSG00000147889.
ENST00000578845; ENSP00000467390; ENSG00000147889.

GeneID

1029.

KEGG

hsa:1029.

UCSC

uc003zpj.3. human.
uc003zpk.3. human.

Organism-specific databases

CTD

1029.

GeneCards

GC09M021957.

HGNC

HGNC:1787. CDKN2A.

HPA

CAB000093.
CAB000445.
CAB018232.

MIM

151623. phenotype.
155601. phenotype.
155755. phenotype.
600160. gene.
606719. phenotype.

neXtProt

NX_P42771.

PharmGKB

PA106.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG42176.

HOGENOM

HOG000290191.

HOVERGEN

HBG050870.

KO

K06621.

OMA

TRGSNHA.

OrthoDB

EOG41ZFC6.

Enzyme and pathway databases

Pathway_Interaction_DB

ar_pathway. Coregulation of Androgen receptor activity.

Reactome

REACT_115566. Cell Cycle.

Gene expression databases

ArrayExpress

P42771.

Bgee

P42771.

CleanEx

HS_CDKN2A.

Genevestigator

P42771.

GermOnline

ENSG00000147889. Homo sapiens.

Family and domain databases

Gene3D

1.25.40.20. 1 hit.

InterPro

IPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
[Graphical view]

Pfam

PF00023. Ank. 1 hit.
PF12796. Ank_2. 1 hit.
[Graphical view]

SMART

SM00248. ANK. 2 hits.
[Graphical view]

SUPFAM

SSF48403. ANK. 1 hit.

PROSITE

PS50297. ANK_REP_REGION. 1 hit.
PS50088. ANK_REPEAT. False negative.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P42771.

GenomeRNAi

1029.

NextBio

4323.

SOURCE

Search...

Entry information

Entry name

CD2A1_HUMAN

Accession

Primary (citable) accession number: P42771
Secondary accession number(s): A5X2G7 , D3DRK1, O95440, Q15191, Q5VVJ5, Q96B52, Q9NP05

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	July 15, 1998
Last modified:	May 1, 2013
This is version 151 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.