Although the exact mechanism(s) by which promoting agents selectively enhance cell replica- tion in preneoplastic cells is unknown, our understanding of the interaction of ligand-receptor signaling with the cell cycle and its regulation has dramatically increased in recent years. Figure 7.9 diagrams an integration of the cell cycle and apoptosis with the signal transduction pathways (Figure 7.6). Phosphorylation of the mitogen-activated protein kinase (MAPK) via the signal transduction pathway activates this kinase (Figure 7.9), which then activates various transcrip- tion factors, the proto-oncogene products, c-myc, c-jun, and c-fos (Seger and Krebs, 1995). Rb, the retinoblastoma tumor suppressor gene, is made throughout the cell cycle. It becomes highly phosphorylated at the beginning of DNA synthesis (G1,S). This releases a transcription factor, E2F, which is complexed with the highly phosphorylated but not the hypophosphorylated Rb protein. E2F then is available to stimulate the transcription of a variety of genes needed for the transition from G1 and the initiation of DNA synthesis. As noted above, ligand-receptor interac- tions can result in the activation of E2F and thus the transcription of genes needed for continuation of the cell cycle. This continuation involves a variety of protein kinases and proteins known as cyclins (cf. Oratta, 1994) that are discussed more exhaustively in Chapters 9 and 15. Another tu- mor suppressor gene, the p53 gene, also plays a role as a transcription factor, preventing continu- ance of the cell cycle on the occasion of DNA damage (Wu and Levine, 1994). Such a pause allows the cells to repair such damage or, if the damage is excessive, to undergo apoptosis (Figure 7.9). If
Figure 7.9 Diagram of the cell cycle and its associated cycle to apoptosis or terminal differentiation with potential to return to the active cycle under the influence of growth factors and related components. Signal transduction may regulate the cell cycle through kinase activation involving the E2F-Rb interaction or other kinases and related molecules involved in the cell cycle (Chapter 9). (From Laird and Shalloway,1997; Müller et al., 1993.)
the p53 gene is mutated or absent, such a pause does not occur and the cell cycle continues replicating despite the presence of damage, resulting in mutations and clastogenesis (Lane,
1992; Sander et al., 1993; Dulic et al., 1994). Obviously, the missing mechanistic link is a clear understanding of the selective enhancement of the cell cycle in preneoplastic cells by promoting agents (Jacobs, 1992). A variety of possibilities exist, including increased concentrations of re- ceptors or any one or more of the components of the signal transduction pathway, as well as mutations in transcription factors, cyclins, cdks, or other components of the cell cycle. As yet, however, definitive studies to pinpoint such mechanisms have not been performed.