Cell cycle checkpoints and cancer

Abstract

Regulation of eukaryoticcell division is under tight control and includes several checkpoints.The controlling elements consist of cyclin-dependent kinases (CDKs) and their activators (cyclins) and inhibitors (INK4 and CIP/KIP).As the cell progresses through the cell cycle, various cyclins appear and bind to specific CDKs.These heterodimeric protein kinases are responsible for shuttling the cell through different regulatory checkpoints along the cell cycle.The major checkpoints include the G1/S checkpoint, which regulates entrance into the S-phase and the duplication of DNA; the G2/M checkpoint, which regulates entrance into mitosis and the alignment of the chromosomes; and the metaphase checkpoint, which regulates entrance into anaphase resulting in chromosome splitting and eventually in cell division.The connection between the cell cycle checkpoints and carcinogenesis involves checkpoint misregulation. This misregulation can lead to unscheduled cell division and cell proliferationand to genomic and chromosome instability associated with tumorigenesis. It is often the product of CDK mutation, overexpression of cyclins, or inactivation of CDK inhibitors. Finally, the mechanism of checkpoint (mis)regulation provides ample targets for developing drugs to treat cancer and represents a fecund area for future therapeutic developments.