Cell Cycle Pathways

The cell cycle consists of a set of highly ordered events that result in cell division and duplication. Multiple extracellular signals induce cells to traverse the cell cycle, through transcription of molecules, which serve as sensors to guide the cell's entry into various phases of cell cycle and division (Fig. 2). A central step in the G1/S transition is the phosphorylation and inactivation of the retinoblastoma gene product (Rb), a tumor suppressor gene product, which results in the release of the E2F1 transcription factor and activation of E2F-responsive genes, such as cyclin E and thymidine kinase, necessary for progression to S phase. Rb phosphorylation occurs by activation of serine/threonine kinases that form complexes with cyclins and are known as cyclin-dependent kinases (CDKs). In turn, CDKs are regulated through a stoichiometric combination with small inhibitory proteins called cyclin-dependent kinase inhibitors (CDKIS), of which two families have been identified: the INK4 (inhibitor of CDK4) family of proteins (p16, p15, p18, and p19) and the KIP (kinase inhibitor protein) family of proteins (p21, p27, and p57) (20), (Fig. 2). Tumors often have aberrations in the Rb pathway, resulting in hyperactivation of CDKs, through mechanisms such as amplification and/or overexpression of positive cofactors (e.g., cyclins/cdks), or downregulation of endogenous CDKIs or mutation of the Rb product. Understanding the structure and dynamics of cell cycle regulatory molecules opens the door for the development of small molecules directly targeted to the catalytic CDK subunit, or the direct manipulation of CDK activity through targeting molecules in the upstream and downstream pathways (Fig. 2). An immediate opportunity is the rational design of small-molecule CDK inhibitors that specifically interact with the ATP binding site (21,22).

Growth factors, mitogens

Growth factors, mitogens

G1 phase-S phase

UCN-01

Fig. 2. Potential mechanisms of drug (shown in boxes) actions involving cell cycle pathways are summarized. Arrows represent positive regulation and bars (!) represent negative regulation. See text for details. CDK, cyclin-dependent kinase; PCNA, proliferating cell nuclear antigen.

G1 phase-S phase

UCN-01

Fig. 2. Potential mechanisms of drug (shown in boxes) actions involving cell cycle pathways are summarized. Arrows represent positive regulation and bars (!) represent negative regulation. See text for details. CDK, cyclin-dependent kinase; PCNA, proliferating cell nuclear antigen.

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