Small molecule regulators of Rb–E2F pathway as modulators of transcription

Abstract

The retinoblastoma tumor suppressor protein, Rb, plays a major role in the regulation of mammalian cell cycle progression. It has been shown that Rb function is essential for the proper modulation of G1/S transition and inactivation of Rb contributes to deregulated cell proliferation. Rb exerts its cell cycle regulatory functions mainly by targeting the E2F family of transcription factors and Rb has been shown to physically interact with E2Fs1, 2 and 3, repressing their transcriptional activity. Multiple genes involved in DNA synthesis and cell cycle progression are regulated by E2Fs, and Rb prevents their expression by inhibiting E2F activity, inducing growth arrest. It has been established that inactivation of Rb by phosphorylation, mutation, or by the interaction of viral oncoproteins lead to a release of the repression of E2F activity, facilitating cell cycle progression. Rb-mediated repression of E2F activity involves the recruitment of a variety of transcriptional co-repressors and chromatin remodeling proteins, including histone deacetylases, DNA methyl transferases and Brg1/Brm chromatin remodeling proteins. Inactivation of Rb by sequential phosphorylation events during cell cycle progression leads to a dissociation of these co-repressors from Rb, facilitating transcription. It has been found that small molecules that prevent the phosphorylation of Rb prevents the dissociation of certain co-repressors from Rb, especially Brg1, leading to the maintenance of Rb mediated transcriptional repression and cell cycle arrest. Such small molecules have anti-cancer activities and will also act as valuable probes to study chromatin remodeling and transcriptional regulation.

Millimeter wave treatment promotes chondrocyte proliferation via G1/S cell cycle transition

“…CDKs are expressed and active in a cell cycle phase-specific manner, such that CDK4 and CDK6 activity is necessary for progression through the G 1 phase (23). Cyclin D1 forms complexes with CDK4 or CDK6, which play an important role in the G 1 /S transition by phosphorylating Rb (24). As a consequence of Rb phosphorylation, E2F is released from the Rb/E2F complexes and then triggers cell progression from the G 1 to S phase (25).…”

Human herpesvirus 6 (HHV-6) alters E2F1/Rb pathways and utilizes the E2F1 transcription factor to express viral genes

“…The binding of hypophosphorylated Rb to E2F1 leads to inhibition of E2F1 transcription activity and cell-growth arrest. In the G1 phase, Rb protein is inactivated following its phosphorylation by cyclin D/CDK-4/6 and cyclin E/CDK-2 complexes, resulting in its dissociation from E2F1/DP1 heterodimer and cellular entry into the S phase (11,12). In midlate S phase, the cyclin A/CDK-2 complex phosphorylates E2F1/ DP1 complex, reducing their DNA binding capacity (10,11).…”

Duhuo Jisheng Decoction promotes chondrocyte proliferation through accelerated G1/S transition in osteoarthritis

“…Progression through the G1 phase of the cell cycle is tightly regulated by the successive activation of D-type cyclins and CDKs (34). Cyclin D1 forms complexes with CDK4 or CDK6, which play an important role in the G1/S transition by phosphorylating Rb (35). As a consequence of Rb phosphorylation, E 2 F is released from the Rb/E 2 F complexes and then triggers cell progression from the G1 to the S phase (36).…”