INK4A

The INK4A gene, also known as CDKN2A, is a tumor suppressor gene located on chromosome 9p21. It plays a critical role in cell cycle regulation and is a key player in preventing uncontrolled cell proliferation. The gene encodes two distinct proteins, p16INK4a and p14ARF, which are generated through alternative splicing and translation from different start codons within the same locus.

p16INK4a functions by inhibiting cyclin-dependent kinases 4 and 6 (CDK4/CDK6). These kinases are essential for the transition from the G1 phase to the S phase of the cell cycle, the period of DNA replication. By blocking CDK4/CDK6 activity, p16INK4a prevents the phosphorylation of the retinoblastoma protein (Rb), thereby halting cell cycle progression and promoting cellular senescence, a state of permanent cell cycle arrest.

p14ARF acts independently of p16INK4a. It stabilizes tumor suppressor proteins p53 by inhibiting the MDM2 protein, which is responsible for p53 degradation. p53 is a crucial guardian of the genome, initiating apoptosis (programmed cell death) in response to DNA damage or other cellular stresses, thus preventing the propagation of potentially cancerous cells.

The INK4A gene is frequently inactivated or mutated in a wide variety of human cancers. This loss of function allows cells to bypass normal checkpoints, leading to uncontrolled growth and the accumulation of genetic abnormalities. Due to its critical role in preventing cancer, the INK4A locus is considered a major tumor suppressor locus. Aberrant methylation of the INK4A promoter is a common mechanism for its silencing in many malignancies.