ABSTRACT
In the past 10 years there has been rapid progress in uncovering the links between gene expression and cell-cycle progression. An understanding of these connections has come about partly as a result of the biochemical characterization of cyclin-dependent kinases (CDK), which drive the cell cycle, and partly because of the detailed characterization of the multitude of factors that constitute the basal transcription machinery. In addition, the role of well-established transcription factors, including pRB, E2F, p53, and c-Myc, which play a prominent role in growth regulation, have undergone further clarification (Dang, 1999; Dyson, 1998; Evan and Littlewood, 1998; 1993; Giaccia and Kastan, 1998; Ko and Prives, 1996). This chapter will emphasize recent advances in our understanding of these and other factors during cell-cycle progression in mammalian cells. Studies in this system are providing a unified view of the regulatory controls based on the sequential activation of CDKs during G1 phase and S phase entry. These kinases progressively inhibit the retinoblastoma (pRB) tumor-suppressor protein and initially promote, and then inhibit, E2F, a transcription factor that displays the properties of an oncogene and tumor suppressor. This leads to the timely activation of genes required for cell-cycle progression. Similarly, Cyclin B/Cdc2 activity inhibits a number of transcriptional regulators during M phase. Two other CDK complexes that have less clear roles in cell-cycle regulation, cyclin H/Cdk7 and cyclin C/Cdk8, modify pol II thereby regulating the intiation and progression of transcription. Recent results further suggest intriguing parallels between the mechanisms that regulate transcription by all three RNA polymerases during the cell cycle and conservation of transcriptional controls between yeast and mammalian cells. Thus, an intricate balance of transcriptional and post-translational controls govern the activity of transcription factors that propel the cell cycle in a unidirectional manner.
