THE RB-E2F INTERACTION & ITS REGULATION BY PHOSPHORYLATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The transition between the G1 and S stages of the mammalian cell cycle requires the transcriptional activation of a number of genes involved in growth and DNA synthesis. This process, primarily carried out by E2F proteins, is tightly regulated in G0 and early G1 by Rb, which inhibits E2F activity and recruits other repressors to E2F promoters. Phosphorylation of Rb by cyclin-dependent kinases leads to its inactivation and subsequent progression through the cell cycle towards division via E2F activation. Accordingly, genetic alterations, either in Rb itself or in the proteins that regulate it, that render Rb constitutively inactive are present in a number of human cancers. Rb inhibits the transcription of E2F genes in part by binding the E2F transactivation domain at the A/B pocket; however, the C-terminal domain (RbC) is also necessary for full Rb activity in growth suppression and E2F transcription and binding assays.