Cell Cycle Regulation

1. Cell Cycle Regulation The cell cycle is regulated by cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CDKIs) and is divided into 4 distinct phases (G1, S, G2, and M). G0 represents exit from the cell cycle. The cell cycle is driven by CDKs, which are positively and negatively regulated by cyclins and CDKIs, respectively. The restriction point governs the transition point beyond which progression through the cell cycle is independent of external stimuli. Adapted from Shah and Schwartz. Clin Cancer Res. 2001;7:2168-2181, with permission.

2. Rb and the G1-S Transition Retinoblastoma gene product (Rb) governs entry into S phase. Hypophosphorylated Rb forms a complex with a group of transcription factors, E2F. When Rb is inactivated by CDK2-, CDK4-, or CDK6-mediated phosphorylation, E2F transcription factors are released, resulting in progression into S phase and transcription of a range of targets involved in chemotherapy sensitivity. Adapted from Shah and Schwartz. Clin Cancer Res. 2001;7:2168-2181, with permission.

3. Apoptosis Members of the Bcl-2 family of proteins may be either antiapoptotic (Bcl-2, Bcl-xL, Mcl-1) or proapoptotic (BAD, Bax, Bak, and others). Bcl-2 and Bcl-xL bind and inhibit Apaf-1 and prevent caspase activation. In the presence of excess Bax, Bcl-2 is displaced from Apaf-1, allowing caspase cleavage and activation. Bax further promotes apoptosis by mediating the release of cytochrome c (Cyto c) from mitochondria; Cyto c activates Apaf-1 and caspase 9 and the cascade of activation of effector caspases, resulting in the cleavage of multiple cellular proteins. From Shah and Schwartz. Clin Cancer Res. 2001;7:2168-2181, with permission.

4. Cell Cycle Inhibitors Flavopiridol UCN-01 Bryostatin-1

5. Cell Cycle Inhibition by Flavopiridol Flavopiridol is a pan–cyclin-dependent kinase (CDK) inhibitor of CDK1 (Cdc2), CDK2, CDK4, and CDK6 at nanomolar concentrations, resulting in cell cycle arrest at both the G1/S and the G2/M transitions.

6. Cell Cycle Inhibition by UCN-01 UCN-01 has cell cycle effects at both the G1/S and G2/M transitions. At G1/S, UCN-01 hypophosphorylates Rb and causes the destruction of free E2F-1 by ubiquitination and targeting for proteasome degradation. The net effect is arrest in G1 and significant reduction in early S-phase proteins. At the G2/M transition, through inhibition of Chk1, UCN-01 increases the activity of cyclin B/Cdc2, resulting in G2 checkpoint abrogation and premature entry into M.

7. Cell Cycle Inhibition by Bryostatin-1 Bryostatin-1 transiently induces p21 and subsequent dephosphorylation and inactivation of CDK2. Bryostatin-1 also decreases expression of cyclin B, preventing Cdc2 activation. The net effect is G2 phase arrest of the cell cycle.