ABSTRACT
Loss of theRB checkpoint is a fundamental step in the development of cancer [1,2]. Loss may occur through direct inactivation of the RB gene itself, or through hyperactivation of CDK4, causing inactivation of RB through uncontrolled phosphorylation. In many human cancers, the HPV protein E6 inactivates RB directly. One way or another, tumor cells lose RB function and upregulate activity of the transcription factor complex referred to as E2F [3] (Figure 1; 4). This allows unscheduled entry into S-phase, and suppression of differentiation and se-
nescence, because E2F directs transcription of genes involved directly in replicating DNA and synthesizing pools of DNA precursors. Dihydrofolate reductase and thymidylate synthase, for example, are targets of E2F activity, along with cyclins A and E, MCM proteins, and many other key regulators of S-phase (Figure 2).
