CDKN2A (Cyclin Dependent Kinase Inhibitor 2A): Tumor Suppressor Gene, p16/p14ARF, and Cancer Risk
A master regulator of cell cycle and apoptosis, frequently altered in melanoma, pancreatic cancer, and other malignancies.
Gene Information Card
| Symbol | CDKN2A |
|---|---|
| Full Name | Cyclin Dependent Kinase Inhibitor 2A |
| Gene Type | Protein coding |
| Chromosomal Location | 9p21.3 |
| NCBI Gene ID | 1029 ncbi.nlm.nih.gov/gene/1029 |
| Ensembl ID | ENSG00000147889 |
| UniProt ID | P42771 (p16INK4a), Q8N726 (p14ARF) |
| OMIM ID | 600160 |
| HGNC ID | 1787 |
| Aliases | p16, p16INK4a, p14ARF, ARF, CDKN2, MTS1, CMM2, INK4a, MLM |
Description
The CDKN2A gene encodes two major protein isoforms, p16INK4a and p14ARF, generated through alternative splicing and distinct reading frames. p16INK4a inhibits cyclin-dependent kinases CDK4 and CDK6, preventing phosphorylation of the retinoblastoma protein (RB1) and thereby blocking cell cycle progression from G1 to S phase. p14ARF stabilizes p53 by inhibiting MDM2-mediated degradation, leading to cell cycle arrest or apoptosis in response to oncogenic stress. CDKN2A is a classic tumor suppressor gene, and its loss or mutation is implicated in various cancers, including familial melanoma, pancreatic cancer, and others.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Melanoma, cutaneous malignant, susceptibility to | Loss of function mutations in CDKN2A lead to uncontrolled cell proliferation and impaired apoptosis, increasing melanoma risk. | ClinVar, OMIM |
| Pancreatic cancer, susceptibility to | Inactivating mutations or deletions of CDKN2A are associated with familial pancreatic cancer, disrupting cell cycle control. | ClinVar, OMIM |
| Melanoma, uveal | Somatic mutations or loss of heterozygosity at CDKN2A contribute to uveal melanoma pathogenesis. | COSMIC, ClinVar |
| Li-Fraumeni syndrome (atypical) | Rare germline mutations in CDKN2A have been reported in Li-Fraumeni-like syndromes, affecting p53 pathway via p14ARF. | OMIM, ClinVar |
| Head and neck squamous cell carcinoma | Frequent deletion or promoter methylation of CDKN2A leads to loss of p16 expression, a common event in HNSCC. | COSMIC, ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skin | Low | Expression is low in normal skin but upregulated in response to cellular stress. |
| Pancreas | Low | Normal pancreatic tissue shows low CDKN2A expression. |
| Lung | Low | Low expression in normal lung tissue. |
| Breast | Low | Low expression in normal breast tissue. |
| Colon | Low | Low expression in normal colon tissue. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | Low | HeLa cells have low CDKN2A expression due to HPV E7-mediated degradation of pRB. |
| A549 (lung cancer) | Low | A549 cells show reduced CDKN2A expression due to promoter methylation. |
| MCF7 (breast cancer) | Low | MCF7 cells have low CDKN2A expression. |
| SK-MEL-28 (melanoma) | Low | Melanoma cell lines often have CDKN2A mutations or deletions. |
| PANC-1 (pancreatic cancer) | Low | Pancreatic cancer cell lines frequently show CDKN2A loss. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p16INK4a R24P | Missense | Rare | Disrupts CDK4/6 binding, leading to loss of cell cycle inhibition. |
| p16INK4a D84Y | Missense | Rare | Alters protein stability and CDK binding. |
| p14ARF R99X | Nonsense | Rare | Truncates p14ARF, impairing MDM2 inhibition and p53 activation. |
| c.151-2A>G | Splice site | Rare | Affects splicing, leading to loss of functional protein. |
| Deletion of entire CDKN2A locus | Copy number loss | Common in somatic tumors | Loss of both p16 and p14ARF, abrogating cell cycle control and apoptosis. |
Mutation functional classification
Loss of Function (LOF)
Most CDKN2A mutations are loss-of-function, resulting in reduced or absent p16/p14ARF activity, leading to uncontrolled cell proliferation and increased cancer risk.
Gain of Function (GOF)
Gain-of-function mutations are rare and not well-documented for CDKN2A; the gene primarily acts as a tumor suppressor.
Dominant Negative (DN)
Some missense mutations in p16INK4a can exert dominant-negative effects by forming inactive complexes with CDK4/6, reducing the pool of functional inhibitor.
View complete mutation data：
Gene Ontology (GO)
| • cyclin-dependent protein serine/threonine kinase inhibitor activity | • protein binding |
| • identical protein binding | • enzyme binding |
| • cell cycle arrest | • G1/S transition of mitotic cell cycle |
| • negative regulation of cell cycle | • negative regulation of cell proliferation |
| • apoptotic process | • cellular response to DNA damage stimulus |
Pathways
• Cell cycle regulation (p16INK4a-CDK4/6-RB pathway)
• p53 signaling pathway (p14ARF-MDM2-p53)
• Senescence and apoptosis
Protein Summary
The CDKN2A gene produces two key proteins: p16INK4a, a cyclin-dependent kinase inhibitor that blocks cell cycle progression by preventing CDK4/6-mediated phosphorylation of RB1, and p14ARF, which stabilizes p53 by inhibiting MDM2, thereby promoting cell cycle arrest or apoptosis. Both proteins are critical tumor suppressors, and their loss is a common event in cancer development.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CDKN2A Knockout HEK293 Cell Line | EDJ-KQ2721 | Human | 1029 | Details Get a Quote |
| CDKN2AIP Knockout HEK293 Cell Line | EDJ-KQ11934 | Human | 55602 | Details Get a Quote |
| CDKN2A Knockout HCT 116 Cell Line | EDJ-KQ22202 | Human | 1029 | Details Get a Quote |
| CDKN2AIP Knockout HeLa Cell Line | EDJ-KQ39198 | Human | 55602 | Details Get a Quote |
| CDKN2A Knockout HeLa Cell Line | EDJ-KQ23576 | Human | 1029 | Details Get a Quote |
| CDKN2AIP Knockout A-549 Cell Line | EDJ-KQ40441 | Human | 55602 | Details Get a Quote |
| CDKN2AIP Knockout HCT 116 Cell Line | EDJ-KQ40442 | Human | 55602 | Details Get a Quote |
| CDKN2A Knockout A-549 Cell Line | EDJ-KQ61334 | Human | 1029 | Details Get a Quote |
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