CDKN2A Gene

CDKN2A (CDKN2A is the acronym for "Cyclin Dependent Kinase Inhibitor 2A") is a protein-coding gene
locatedon chromosome9p21
.3. The CDKN2A gene produces 3 transcript variants that differ in their first exons. They code for different proteins. Two transcript variants encode structurally related isoforms that function as inhibitors of CDK4 kinase. The remaining transcript contains an alternative open reading frame (ARF) encoding a protein that functions as a stabilizer of the tumor suppressor protein p53. Despite structural and functional differences, the CDK inhibitor isoforms and the ARF product share a common function in cell cycle control in G1 progression.

• CDKN2A is able to arrest the cell cycle in phases G1 and G2.
• Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering in the nucleolus. This inhibits the oncogenic effect of MDM2 by blocking MDM2-induced degradation of p53 and promoting p53-dependent transactivation and apoptosis.
• CDKN2A also triggers G2 arrest and apoptosis in a p53-independent manner by preventing activation of cyclin B1/CDC2 complexes.
• Binds to BCL6 and downregulates BCL6-induced transcriptional repression.
• Binds to E2F1 and MYC and blocks their transcriptional activator activity.
• Binds to TOP1/TOPOI and stimulates its activity.
• Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, inhibiting rRNA processing.
• Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination.
• Interacts with UBE2I/UBC9 and enhances sumoylation (this involves attaching SUOMO = small ubiquitin-related modifiers to other proteins, altering their biological functions) of a number of its binding partners, including MDM2 and E2F1.
• Binds to HUWE1 and suppresses its ubiquitin ligase activity.
• May play a role in the control of cell proliferation and apoptosis during mammary gland development.
• Acts to negatively regulate proliferation of normal cells by strongly interacting with CDK4 and CDK6. This inhibits their ability to interact with cyclin D and phosphorylate the retinoblastoma protein.

The CDKN2A gene is mutated or deleted in a variety of tumors and is considered an important tumor suppressor gene. In the majority of cases, CDKN2A is inactivated by homozygous deletions. This results in hypermethylation of the promoter region of the gene. The prognostic implications of promoter hypermethylation are as yet unclear. However, many studies have shown that patients with hypermethylation in colorectal, liver, younger lung cancer patients and leukemias (Agarwal M et al. 2018) have a worse prognosis.

Diseases associated with CDKN2A include FAMM syndrome.

In addition, CDKN2A (p16) expression is a surrogate marker for HPV infection.

1. Agarwal M et al. (2018) Cyclin dependent kinase inhibitor 2A/B gene deletions are markers of poor prognosis in Indian children with acute lymphoblastic leukemia. Pediatr Blood Cancer 65:e27001.
2. Davis EJ et al (2018) Melanoma: what do all the mutations mean? Cancer 124:3490-3499.
3. Kahoul Y et al. (2020) Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes. Biomolecules 10:1350.
4. Zhao R et al. (2016) Implications of Genetic and Epigenetic Alterations of CDKN2A (p16(INK4a)) in Cancer. EBioMedicine 8:30-39.