p16 inhibits cyclin dependent kinases 4 and 6 (CDK4 and CDK6) and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase.

[12] p16 comprises four ankyrin repeats, each spanning a length of 33 amino acid residues and, in the tertiary structure, forming a helix-turn-helix motif.

[16] P14ARF induces cell cycle arrest in G2 phase and subsequent apoptosis in a P53-dependent and P53-independent manner, and thus is regarded as a tumor suppressor.

[22][23] P16/Rb pathway collaborates with the mitogenic signaling cascade for the induction of reactive oxygen species, which activates the protein kinase C delta, leading to an irreversible cell cycle arrest.

[24][25] On the other hand, some specific tumors harbor high levels of P16, and its function in limitation of tumorigenic progression has been inactivated via the loss of Rb.

[25][26] In human cancer cell lines derived from various tumor types, a high frequency of genetic and epigenetic alterations (e.g., promoter hyper-methylation, homozygous deletion or mutation) in the CDKN2A gene has been observed.

First, this region is well known in cancer genetics as one of the most common sites of deletions leading to hereditary forms of cutaneous malignant melanoma.

When working normally, p16 binds to the cyclin dependent kinases CDK4 to inhibit their ability to create tumors, but when inactivated the suppression no longer occurs.

[44] This is because the factors mentioned earlier pertaining to those who are more susceptible to the disease and also dependent on the amount of sunscreen one wears and the UV radiation potency in their environment.

[43] A multi-locus genetic risk score study based on a combination of 27 loci, including the CDKN2A gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy.

[9] Activation of the CDKN2A locus promotes the cellular senescence tumor suppressor mechanism, which is a permanent form of growth arrest.

[46] A variant in the CDKN2A locus present in the founder of Bernese mountain dogs around 200 years ago predisposes the breed to histiocytic sarcoma.