Cell Cycle Control
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CELL CYCLE CONTROL Vivien J. Tannoch1, Phil W. Hinds1, and Li-Huei Tsai1,2 1
Harvard Medical School Department of Pathology 200 Longwood Ave Boston Massachusetts 02115 2 Howard Hughes Medical Institute
200 Longwood Ave Boston Massachusetts 02115
1. INTRODUCTION Regulation of the cell cycle is maintained through a delicately balanced array of
mechanisms. These regulatory mechanisms extend from controlling the actual transcription of genes encoded in the genome, to regulating the catalytic activity of enzymes in the cell. This chapter will highlight specific examples of these control-ling mechanisms, the cell cycle machinery, and discuss some of the genes that are deregulated in disease states, such
as cancer, which involves the deregulation of normal cell proliferation. Our understanding of the cell cycle was substantially increased when the cyclins and cyclin-dependent kinases (cdks) were discovered (Sherr, 1993; Sherr, 1996). These proteins have multiple family members, and together the cyclins and cdks form active holoenzymes capable of phosphorylating their specific substrates. Progression through
each phase of the cell cycle is tightly correlated with the expression and rapid degradation of these cyclin-cdk complexes. This tight regulation of the cyclin-cdk complexes is critical since it is their catalytic activity that determines the phosphorylation status of other proteins important in the regulation of the cell cycle. One such protein is the retinoblastoma (pRb) protein (Mittnacht, 1998). The Rb gene was originally identified as a tumour suppressor that was genetically mutated in families with a predisposition to
retinoblastoma and osteosarcomas (Friend et al., 1986). pRb is now recognised to exert potent control over cell cycle progression from Gl to the S phase. This is in part due to the ability of pRb to bind, and modulate the activity of transcription factors such as
E2F, which are important in the regulation of gene transcription (Dyson, 1998; Nevins, 1992). The phosphorylation of pRb controls its ability to bind these transcription factors (Knudsen and Wang, 1997; Mittnacht, 1998). Release of the transcription factors by
phosphorylation of pRb permits the activation, or de-repression, of transcription of yet other genes encoding proteins of importance in cell proliferation. Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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Thus we are beginning to understand how the cell cycle is controlled by a wide variety of proteins which are in turn regulated by a number of mechanisms including phosphorylation and proteolytic degradation, all of which are critical to the successful completion of the cell cycle, see Fig. 1. This multi-layered complexity in the regulation of the cell cycle also allows the cell to decide when not to proceed with cell division due to problems in the cell (Elledge, 1996; Paulovich, Toczyski, and Hartwell, 1997). For example, DNA damage will trigger the normal cell
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