DNA Damage Retinoblastoma and Cell Survival

点击翻译按钮获取中文摘要

DESCRIPTION: (provided by applicant) The Retinoblastoma (Rb) gene is functionally inactivated in many forms of cancer, like breast carcinoma and small cell lung carcinoma, and represents the prototypical tumor suppressor. In addition to its tumor suppressor activity Rb inhibits cell cycle progression, is essential for induction of cell cycle arrest after DNA damage and inhibits cell death. The complexity of biological effects of Rb is matched by the diversity of: proteins which bind Rb. Rb binds a number of proteins, including E2F-1, oncoviral proteins like the SV4O large T antigen, c-Abl, MDM2 and histone deacetylases. Although the observation that Rb inhibits cell death is almost nine years old, our understanding of the underlying molecular mechanisms remain obscure. We have found Rb mutants which retain the ability to inhibit cell cycle progression but do not promote cell survival after DNA damage. These studies have led us to propose a model of the anti-apoptotic activity of Rb in which the ability of Rb to promote cell survival after DNA damage is mediated by the LxCxE binding site of Rb. In this proposal we will further develop our hypothesis that the Rb-LxCxE interaction plays an essential role in cell survival after DNA damage. We will examine the generality of Rb-LxCxE interaction in cell survival after DNA damage and establish its biological significance by generating Rb -I- mice which express a mutant Rb transgene that is unable to bind LxCxE motif containing proteins. We will characterize the apoptosis signaling pathways engaged by Rb (Rb-LxCxE interaction) to promote cell survival. The relationship between the Rb-LxCxE interaction and other Rb binding proteins in the Rb survival pathway will also be clarified. These studies will impact our understanding of Rb in its cell biological functions and in human cancer.