Tumor surveillance via the ARF–p53 pathway
- Howard Hughes Medical Institute, Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 USA
This extract was created in the absence of an abstract.
The retinoblastoma (Rb) and p53genes are not essential for completion of the cell division cycle, but disruption of their functions is central to the life history of most, if not all, cancer cells (for review, seeWeinberg 1995; Sherr 1996; Levine 1997). Surprisingly, Rb and p53 are themselves regulated by two proteins encoded by a single genetic locus, INK4a/ARF, the products of which, p16INK4a and p19ARF, are also potent tumor suppressors. The role of p16INK4a as an inhibitor of cyclin D-dependent kinases has been appreciated since its discovery (Serrano et al. 1993). Now, emerging evidence is providing valuable insights into the molecular circuitry through which p19ARF modulates p53 activity as part of a checkpoint response to oncogenic, hyperproliferative signals.
Regulation of cell cycle progression by pRb and p53
During most of G1 phase of the mammalian cell cycle, Rb in its hypophosphorylated form binds to several transcription factors of the E2F family, constraining their activity on some promoters and actively repressing transcription from others (see Dyson 1998). Phosphorylation of Rb by cyclin-dependent kinases (cdks) in the mid-to-late G1 phase of the cycle untethers Rb from the E2Fs. In turn, this enables the E2Fs to activate a series of target genes, the expression of which is required for cells to enter S phase, thereby stimulating proliferation (Fig. 1). The cyclin D-dependent kinases cdk4 and cdk6 trigger Rb phosphorylation, which is likely completed by cyclin E–cdk2 as cells approach the G1-to-S phase transition. Because induction and assembly of cyclin D-dependent kinases is dependent on mitogenic signaling, cancellation of Rb’s growth-suppressive activity is coupled to extracellular stimuli. By inhibiting cdk4 and cdk6, a family of INK4 proteins can prevent cells with functional Rb from entering S phase. The prototypic member, p16INK4a(Serrano et al. 1993), is …
