Inactivation of the retinoblastoma tumor suppressor in humans (RB) and in mice (Rb) facilitates neoplastic progression. To a large part, pRB regulates growth by repressing E2F/DP famil) complexes, a subset of which when free, stimulates cell cycle progression. Instead, pRB stimulates differentiation by regulating transcription factors responsible for specific differentiation programs (e.g., activation of MyoD, C/EBP, CBFA1). Yet, loss of pRB does not compromise the development of all tissues, and germ-line RB or Rb mutations lead to highly penetrant, tissue specific tumor predisposition. In vitro, the extent of Gl Cyclin/Cdk-mediated phosphorylation governs the ability of pRB to restrain cell cycle progression; however, the recently demonstrated dispensability of Gl Cyclins and Cdks for the normal development of most tissues; raises the question of what is the """"""""wiring"""""""" that normally regulates the pRB/E2F/DP pathway in vivo. It is likely that the unique tumor suppressive function of pRB (among pRB family numbers) stems from its ability to coordinate growth inhibition with specific lineage commitment. Only by identifying the signals operating in vivo can we understand how loss of Rb disrupts the development of key tissues and facilitates tumorigenesis at specific sites. First, using our novel series of wildtype and mutant Rb promoter transgenics and a new Rb promoter knock-in allele, we will identify the activators and repressors that normally regulate the neuronal-specific expression of Rb and test the functional consequences of deregulating Rb expression in vitro and vivo (Aim 11. Second, we will define a requirement for the entire DP family and its individual family members (Dpi and Dpi) in cell cycle control and embryonic development through siRNA-mediated knockdown of DP family expression and the establishment of conditional Dpi and/or Dp2 knockout mice (Aim 2).
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