The Cell-Cycle Regulator CDK4: An Emerging Therapeutic Target in Melanoma

CDK4 pathway. In response to mitogenic signaling, CDK4 and CDK6 associate with cyclin D to form active complexes that phosphorylate the retinoblastoma protein (RB1). Subsequent phosphorylation of RB1 by CDK2–cyclin E complex allows transcription of E2F regulated genes and transcription of both ribosomal and small RNAs by RNA polymerases. Phosphorylation of RB1 also inhibits its ability to induce senescence. p16^INK4A and p14^ARF are transcribed from the same gene (CDKN2A) and regulate cell-cycle progression by inhibiting CDK4/6 and CDK2 activity, respectively. Induction of p14^ARF inhibits HDM2-mediated degradation of p53, thus increasing expression of p21, which then inhibits CDK2/cyclin E activity. p16^INK4A negatively regulates the cell cycle by specifically inhibiting the assembly and activation of cyclin D–CDK4/6 complexes. Further control of this pathway is via a negative feedback loop whereby CDK4/6 inactivation of RB1 relieves RB1-mediated suppression of p16^INK4A. In addition to the canonical CDK4 pathway, active CDK4/6–cyclin D complexes can directly phosphorylate and regulate transcription factors, including Smad3, MYC, and FOXM1 as well as MEP50, a PRMT5 coregulatory factor, resulting in RB1-independent regulation of cell-cycle progression, senescence, and apoptosis.