Figure 3.

The CDKN2A-CDKN2B locus regulates the cell cycle. Genomic organization of the 9p21 locus containing CDKN2B encoding p15^INK4B and CDKN2A encoding p14^ARF and p16^INK4A. p14^ARF is coded by exons E1β, E2, and E3 and p16^INK4A is coded by exons E1α, E2, and E3. E2 and E3 are shared by p14^ARF and p16^INK4A, but they use alternate reading frames to produce unique protein sequences. p15^INK4B and p16^INK4A induce cell cycle arrest by complexing to CDK4 and CDK6 and preventing their complex formation with cyclin D. Rb remains active (dephosphorylated) and prevents E2F-mediated transcription of target genes necessary for cell cycle progression from G1 to S phase. p14^ARF inhibits cell cycle progression and activates apoptosis by inhibiting MDM2, which leads to activation of p53.