The Retinoblastoma gene Rb was the first tumor suppressor gene cloned, and it is well known as a negative cell cycle regulator. A simplified model for Rb function is that it blocks cell cycle progression by binding to the E2F transcription factors and recruiting co-repressor complexes to repress the expression of E2F target genes. Both E2F and Rb have multiple family members, with specific members of the Rb family capable of binding only to a specific subset of the E2F family. In addition, different E2F proteins exhibit distinct capacities to regulate natural E2F targets due to their different ability to interact with other transcription factors which are also required for the activation of particular E2F target genes. Although Rb and E2F are best known for their cell cycle roles, recent genome wide analysis of E2F targets has suggested that E2F and Rb control not only genes important in the cell cycle but also genes involved in apoptosis, differentiation, and development. Consistent with these observations, analysis of mice and Drosophila with mutations in the Rb and E2F genes has revealed important roles of E2F and Rb proteins in all these areas.

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