CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family member p16 (or p16INK4a) and p14arf. Both act as tumor suppressors by regulating the cell cycle. 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. p14ARF (known as p19ARF in the mouse) activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2A are associated with familial melanoma, glioblastoma and pancreatic cancer. The CDKN2A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. Structure Gene The CDKN2A gene resides on chromosome 9 at the band 9p21 and contains 8 exons. This gene encodes two proteins, p16 and p14ARF, which are transcribed from the same second and third exons but alternative first exons: p16 from exon 1α and ARF from exon 1β. As a result, they are translated from different reading frames and therefore possess completely different amino acid sequences. In addition to p16 and ARF, this gene produces 4 other isoforms through alternative splicing. Proteins p16 This protein belongs to the CDKN2 cyclin-dependent kinase inhibitor family. 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. One exception is the second ankyrin repeat, which contains only one helical turn. These four motifs are connected by three loops such that they are oriented perpendicular to the helical axes. According to its solvent-accessible surface representation, p16 features clustered charged groups on its surface and a pocket located on the right side with a negatively charged left inner wall and a positively charged right inner wall. p14ARF The size of this protein is 14 kDa in humans. Within the N-terminal half of ARF are highly hydrophobic domains that serve as mitochondrial import sequences. Function P14ARF P14ARF is a central actor of the cell cycle regulation process as it participates to the ARF-MDM2-p53 pathway and the Rb-E2F-1 pathway. It is the physiological inhibitor of MDM2, an E3 ubiquitin ligase controlling the