CDKN2A

What is cdkn2a protein?

CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) is a protein coding gene that plays a crucial role in regulation of the cell cycle, specifically in the transition from the G1 to the S phase. The protein that the CDKN2A gene codes for chiefly functions as a tumor suppressor, that is, it prevents cells from growing and dividing in an uncontrolled way. Mutations in this gene can lead to several types of cancer, including familial melanoma, pancreatic cancer, and lung cancer.

The protein produced by the CDKN2A gene is known as p16 or p16INK4a. This protein works by binding to a complex formed by CDK4 or CDK6 and cyclin D, effectively inhibiting the enzymatic activity of CDK4/6 and hence preventing the cell cycle progression.

In terms of its discovery, CDKN2A was first reported in 1994 by several research groups who identified its deletion or mutation in several types of cancers. Originally identified as a protein inhibiting CDK4 (thus the name INK4), the discovery of its role in cancer has led to it being one of the most extensively studied genes in the fields of cancer biology and genetics.

As for its structure, p16INK4a is a member of the INK4 family of proteins which consist of several ankyrin repeats. Ankyrin repeats are a common structural motif in proteins and are composed of two alpha helices separated by loops. In the case of p16INK4a, the protein has four ankyrin repeats, which contribute to its function by allowing it to bind to CDK4/6. Also noteworthy is the gene's location on chromosome 9p21, a region often found deleted in various types of cancer.

What is the function of CDKN2A protein?

CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) protein is a tumor suppressor protein that is involved in regulating the cell cycle. More specifically, it prevents the cell from entering the S phase (where DNA is replicated) from the G1 phase (the step before replication) until the cell is ready to replicate its DNA. This allows the cell to repair any DNA damage before replication and prevents the replication of damaged DNA, thereby preventing the development of cancer. Mutations in the CDKN2A gene that reduce or eliminate the function of this protein can allow cells to grow and divide in an uncontrolled way and can contribute to the development of cancer.

Cdkn2a related signaling pathway

RB tumor suppressor pathway: When induced, p16INK4a binds and inhibits CDK4/6, preventing phosphorylation of RB protein. Unphosphorylated RB remains bound to E2F transcription factors, blocking cell cycle progression from G1 to S phase.

p53 tumor suppressor pathway: Oncogene-induced cellular stresses can trigger p16INK4a expression via p53, inducing senescence by blocking CDK4/6. This enforces permanent cell cycle withdrawal.

AKT/mTOR pathway: Inhibition of CDK4/6 by p16INK4a decreases release of feedback inhibition on PI3K/AKT signaling. Lowered AKT activation subsequently reduces mTORC1 activity, impacting protein synthesis and cell growth.

CDKN2A Related Diseases

•  Cancer predisposition: CDKN2A mutations are associated with increased risk of developing numerous cancers like melanoma, pancreatic cancer, and glioma.
•  Familial melanoma syndrome: Germline mutations in CDKN2A significantly predispose to hereditary melanoma.
•  Pancreatic cancer: Somatic mutations and deletions in CDKN2A are frequently observed in pancreatic ductal adenocarcinoma.
•  Glioma: Reduced p16INK4a expression due to promoter methylation promotes glioma development.
•  Activation holds promise against cancers with CDKN2A loss.
•  Biomarker: Expression/mutation analysis aids prognosis, surveillance of cancer progression/recurrence in melanoma, pancreatic cancer etc.
•  Diagnostics: Genetic testing for CDKN2A variants helps diagnosis of familial cancer syndromes like melanoma syndrome.
•  Drug development: Screening drugs that can induce CDKN2A to trigger senescence in cancer cells or slow aging.

•  Activation holds promise against cancers with CDKN2A loss.
•  Biomarker: Expression/mutation analysis aids prognosis, surveillance of cancer progression/recurrence in melanoma, pancreatic cancer etc.
•  Diagnostics: Genetic testing for CDKN2A variants helps diagnosis of familial cancer syndromes like melanoma syndrome.
•  Drug development: Screening drugs that can induce CDKN2A to trigger senescence in cancer cells or slow aging.