E2F is not the sole target of RB. The versatile RB protein binds to a variety of other transcription factors that regulate cell differentiation. For example, RB stimulates myocyte-, adipocyte-, melanocyte-, and macrophage-specific transcription factors. Thus, the RB pathway couples control of cell cycle progression at G1 with differentiation, which may explain how differentiation is associated with exit from the cell cycle.
In view of the centrality of RB to the control of the cell cycle, an interesting question is why RB is not mutated in every cancer. In fact, mutations in other genes that control
PPPPPPPPPPE2F site S phase genes Stimulate Inactivate ActivateCDK Inhibitors p16 Cyclins D/CDK4,6 Cyclin E/CDK2 Cyclins D/CDK4,6 Cyclin E/CDK2 E2F Hyperphosphorylated RB Hypophosphorylated RB GROWTH FACTORS (EGF, PDGF) GROWTH INHIBITORS (TGF-˜, p53, others) E2F E2F site Histone deacetylase Histone methyl-transferase S phase genes
Fig. 6.20 TheroleofRBinregulatingtheG1–Scheckpointofthecellcycle.HypophosphorylatedRBincomplexwiththeE2FtranscriptionfactorsbindstoDNA,recruitschromatinremodelingfactors(histonedeacetylasesandhistonemethyltransferases),andinhibitstranscriptionofgeneswhoseproductsarerequiredfortheSphaseofthecellcycle.WhenRBisphosphorylatedbythecyclinD–CDK4,cyclinD–CDK6,andcyclinE–CDK2complexes,itreleasesE2F.ThelatterthenactivatestranscriptionofS-phasegenes.ThephosphorylationofRBisinhibitedbyCDKIs,becausetheyinactivatecyclin-CDKcomplexes.VirtuallyallcancercellsshowdysregulationoftheG1–ScheckpointasaresultofmutationinoneoffourgenesthatregulatethephosphorylationofRB;thesegenesareRB, CDK4, cyclin D, and CDKN2A [p16]. EGF, Epidermalgrowthfactor;PDGF, platelet-derivedgrowthfactor.
RB phosphorylation can mimic the effect of RB loss and are commonly found in many cancers that have normal RB genes. For example, mutational activation of CDK4 and overexpression of cyclin D favor cell proliferation by facilitating RB phosphorylation and inactivation. Indeed, cyclin D is overexpressed in many tumors because of amplification or translocation of the cyclin D1 gene. Mutational inactivation of genes encoding CDKIs also can drive the cell cycle by removing important brakes on cyclin/ CDK activity. As mentioned earlier, the CDKN2A gene, which encodes the CDK inhibitor p16, is an extremely common target of deletion or mutational inactivation in human tumors.
It is now accepted that loss of normal cell cycle control is central to malignant transformation and that at least http://ebooksmedicine.net one of the four key regulators of the cell cycle (p16, cyclin D, CDK4, RB) is mutated in most human cancers. Notably, in cancers caused by certain oncogenic viruses (discussed later), this is achieved through direct targeting of RB by viral proteins. For example, the human papillomavirus (HPV) E7 protein binds to the hypophosphorylated form of RB, preventing it from inhibiting the E2F transcription factors. Thus, RB is functionally deleted, leading to uncontrolled growth.
Likeothertumorsuppressorgenes,bothcopiesofRB mustbedysfunctionalfortumordevelopmenttooccur.