Abstract IA21: Mitogenic signaling and the RB/p53 network

Cells entering the division cycle from a quiescent state (G0) in response to mitogenic cues synthesize one or more D-type cyclins (D1, D2, D3) that assemble in G1 phase with cyclin-dependent kinases CDK4 and/or CDK6. Notably, the transcription, assembly with CDK 4/6, and stability of D-type cyclins are each mitogen-dependent steps. Accumulation of cyclin D-dependent kinases in G1 phase leads to the progressive phosphorylation of the retinoblastoma protein (RB), facilitating transcription of E2F-responsive genes, including cyclins E and A, whose CDK2-dependent functions are normally required in S phase. Moreover, the stoichiometric sequestration of CDK2 inhibitors, p27Kip1 and p21Cip1, by cyclin D-dependent kinases, further enables CDK2 activation as well as SCFSkp2-dependent p27 degradation as cells approach the G1/S boundary. In G0, RB remains unphosphorylated, and E2F-responsive genes are repressed by the DREAM complex, which includes E2F-4/5, at least one retinoblastoma family member (RBL2/p130), and the MuvB complex. An open question is whether CDK4 and CDK6 are responsible, at least in part, for dissolution of the DREAM complex or relief of p130/E2F repression in early G1 phase. Cells in G0 and G1 express the APCCDH1 E3 ubiquitin ligase that prevents accumulation of the mitotic cyclins, A and B, prior to S phase entry. As cells near the G1/S transition, APCCDH1 is inactivated by CDK2 in conjunction with the E2F-responsive early mitotic inhibitor EMI1.Cyclin D-CDK4/6 comp...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Keynote Address: Oral Presentations - Invited Abstracts Source Type: research