Figure 1. AR-cell cycle crosstalk.

Activated AR stimulates the accumulation of cyclin D1 (D1), through mammalian Target of Rapamycin (mTOR), to activate CDK4 and promote phosphorylation of the retinoblastoma (RB) tumor suppressor. In addition, AR-induced expression of p21^Cip1 and degradation of p27^Kip1 further enhance cycD1/CDK4 and cycE/CDK2-dependent inactivation of RB and allow expression of E2F target genes like cyclin A (CycA). Cyclin A in turn activates CDK2 to drive G1-S phase transition. Subsequently engaged components of the cell cycle machinery then impinge on AR to regulate the androgen response. Elevated cyclin D1 acts as in a negative feedback loop to attenuate AR activity, thereby modulating androgen action. In G2-phase, CDK1 promotes the phosphorylation and activation of AR. However, AR is degraded in M-phase and is purposed to be a “licensing factor” for DNA replication. Components that suppress AR function are outlined in red, whereas positive effectors of AR activity are outlined in green.