Specific in vivo roles for E2Fs in differentiation and development

E2Fs have been historically considered as key interacting factors for the retinoblastoma (Rb) family of pocket proteins, acting as universal regulators of cell cycle progression. Often exhibiting overlapping function, deregulated E2F activity is thought to cancer or cell death. While early reports hypothesized that E2Fs may be capable of regulating distinct functions beyond proliferation, several recent reports have characterized increasingly diverse, context dependent functions for different E2Fs in vivo, often in what appears to a manner beyond traditional cell cycle regulation. Ironically, many of these new functions are still mediated through the classical cell cycle regulatory Rb family of interacting factors. Here we review the recent advances, focusing on differentiation and development, to emphasize that E2F function is likely more complex than the simple model suggests, capable of exhibiting both specificity of function, and roles beyond cell cycle progression in vivo.