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This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]
CDKN2A loss has been shown to be a significant event in a number of cancer types. While no targeted therapeutic has been engaged in clinical trials, the prognostic impact has been studied by a number of meta-analyses. In majority of cases CDKN2A is inactivated by homozygous deletions. One of the mechanisms by which loss of CDKN2A can occur is by hypermethylation of the promoter region for the gene. However, the prognostic impact of promoter hypermethylation has been relatively ambiguous. Many studies have suggesting poorer prognostic outcome for patients with hypermethylation in colorectal, liver, and younger lung cancer patients. This being said, there is still research to be done before this becomes a widely-accepted prognostic indicator. Additionally, CDKN2A (p16) expression is a surrogate marker for HPV infection. As such, CDKN2A expression is prognostic in Oropharyngeal and probably also non-oropharyngeal head and neck squamous cell carcinomas.
CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) is a Protein Coding gene. Diseases associated with CDKN2A include Melanoma, Cutaneous Malignant 2 and Melanoma-Pancreatic Cancer Syndrome. Among its related pathways are Cellular Senescence (REACTOME) and Regulation of TP53 Activity. Gene Ontology (GO) annotations related to this gene include transcription factor binding. An important paralog of this gene is CDKN2B.
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0003677 | DNA binding | IEA | -- |
GO:0003723 | RNA binding | HDA | 22681889 |
GO:0004861 | cyclin-dependent protein serine/threonine kinase inhibitor activity | IDA | 7739547 |
GO:0005515 | protein binding | IPI | 9751050 |
GO:0008134 | transcription factor binding | IPI | -- |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0005634 | nucleus | IDA | 16243918 |
GO:0005654 | nucleoplasm | TAS | -- |
GO:0005730 | nucleolus | IEA | -- |
GO:0005737 | cytoplasm | IDA | 16243918 |
GO:0005739 | mitochondrion | IEA | -- |
SuperPathway | Contained pathways | ||
---|---|---|---|
1 | Glioma |
.50
.46
|
|
2 | Cyclins and Cell Cycle Regulation |
Cyclins and Cell Cycle Regulation
.67
G1-S Phase Transition
.67
|
.31
|
3 | Cellular Senescence (REACTOME) | ||
4 | SUMOylation |
.95
|
|
5 | Bladder cancer |
.66
|
.66
|
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000082 | G1/S transition of mitotic cell cycle | IDA | 10208428 |
GO:0000209 | protein polyubiquitination | IDA | -- |
GO:0001953 | negative regulation of cell-matrix adhesion | IMP | 10205165 |
GO:0006364 | rRNA processing | IEA | -- |
GO:0006469 | negative regulation of protein kinase activity | IMP | -- |
Name | Status | Disease Links | Group | Role | Mechanism of Action | Clinical Trials |
---|---|---|---|---|---|---|
BAY1000394 | Pharma | Inhibition, Biomarker | CDK4 Inhibitors, CDK2 Inhibitors | 0 | ||
LEE011 | Pharma | inhibitor, Biomarker | CDK4/6 inhibitor, CDK4 Inhibitors, Kinase Inhibitors | 0 | ||
LY2835219 | Pharma | Inhibition, inhibitor, Biomarker | CDK4/6 inhibitor,potent and selective, CDK4/6 inhibitor, CDK4 Inhibitors | 0 | ||
PD 0332991 | Pharma | Biomarker | CDK4 Inhibitors | 0 |
Name | Synonyms | Role | CAS Number | PubChem IDs | PubMed IDs |
---|
ExUns: | 1a | · | 1b | · | 1c | ^ | 2 | ^ | 3a | · | 3b | ^ | 4 | ^ | 5a | · | 5b | · | 5c | ^ | 6 | ^ | 7a | · | 7b | · | 7c | ^ | 8a | · | 8b | · | 8c | · | 8d |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SP1: | - | - | - | - | - | - | - | - | - | ||||||||||||||||||||||||||
SP2: | - | - | - | - | |||||||||||||||||||||||||||||||
SP3: | - | - | - | ||||||||||||||||||||||||||||||||
SP4: | - | - | - | - | - | - | - | - | - | - | |||||||||||||||||||||||||
SP5: | - | ||||||||||||||||||||||||||||||||||
SP6: | - | - | - | - | - | - | - | - | - | ||||||||||||||||||||||||||
SP7: | - | ||||||||||||||||||||||||||||||||||
SP8: | - |
This gene was present in the common ancestor of chordates.
Organism | Taxonomy | Gene | Similarity | Type | Details |
---|---|---|---|---|---|
chimpanzee (Pan troglodytes) |
Mammalia | CDKN2A 33 32 |
|
OneToOne | |
dog (Canis familiaris) |
Mammalia | CDKN2A 32 |
|
||
cow (Bos Taurus) |
Mammalia | CDKN2A 33 32 |
|
OneToOne | |
rat (Rattus norvegicus) |
Mammalia | Cdkn2a 32 |
|
||
mouse (Mus musculus) |
Mammalia | Cdkn2a 17 32 |
|
||
platypus (Ornithorhynchus anatinus) |
Mammalia | -- 33 |
|
OneToMany | |
oppossum (Monodelphis domestica) |
Mammalia | -- 33 |
|
ManyToMany | |
CDKN2A 33 |
|
ManyToMany | |||
chicken (Gallus gallus) |
Aves | CDKN2B 33 |
|
OneToMany | |
lizard (Anolis carolinensis) |
Reptilia | -- 33 |
|
OneToMany | |
tropical clawed frog (Silurana tropicalis) |
Amphibia | cdkn2b 32 |
|
||
zebrafish (Danio rerio) |
Actinopterygii | LOC100329528 32 |
|
||
BX323448.2 33 |
|
ManyToMany |
SNP ID | Clin | Chr 09 pos | Variation | AA Info | Type |
---|---|---|---|---|---|
rs1001405220 | uncertain-significance, Hereditary cutaneous melanoma | 21,971,101(-) | G/A/T | 3_prime_UTR_variant, coding_sequence_variant, missense_variant, non_coding_transcript_variant, synonymous_variant | |
rs1014358179 | likely-benign, uncertain-significance, Hereditary cutaneous melanoma, Hereditary cancer-predisposing syndrome | 21,994,180(-) | C/G | coding_sequence_variant, genic_upstream_transcript_variant, intron_variant, missense_variant | |
rs1016841954 | likely-benign, Hereditary cutaneous melanoma | 21,974,717(-) | C/T | coding_sequence_variant, genic_upstream_transcript_variant, intron_variant, non_coding_transcript_variant, synonymous_variant | |
rs1025333664 | uncertain-significance, Hereditary cancer-predisposing syndrome | 21,974,672(-) | A/G | coding_sequence_variant, genic_upstream_transcript_variant, intron_variant, synonymous_variant | |
rs1034265990 | uncertain-significance, Hereditary cancer-predisposing syndrome, Hereditary cutaneous melanoma | 21,971,123(-) | G/A/T | 3_prime_UTR_variant, coding_sequence_variant, missense_variant, non_coding_transcript_variant, synonymous_variant |
Variant ID | Type | Subtype | PubMed ID |
---|---|---|---|
esv1425040 | CNV | deletion | 17803354 |
esv2764150 | CNV | gain+loss | 21179565 |
nsv1018514 | CNV | gain | 25217958 |
nsv8426 | CNV | loss | 18304495 |
Disorder | Aliases | PubMed IDs |
---|---|---|
melanoma, cutaneous malignant 2 |
|
|
melanoma-pancreatic cancer syndrome |
|
|
melanoma-astrocytoma syndrome |
|
|
dysplastic nevus syndrome |
|
|
leukemia, acute lymphoblastic 3 |
|