The overall hypothesis of this research proposal is that cellular quiescence and oncogene-induced senescence serve as critical barriers to cancer. We propose that RB and the RB-related DREAM complex contribute independent, distinct and essential growth suppression activities during cellular quiescence and oncogene-induced senescence. To identify their unique contributions to quiescence and senescence, we will selectively perturb RB and DREAM using a variety of genetic and biochemical approaches including expression of SV40 large T antigen (LT) point substitution mutants. In addition, we will determine if LT cooperates with several, newly identified, LT-interacting host cell factors to disrupt the DREAM complex and transform cells.
Specific Aims (1) Distinguish the role of RB and DREAM in quiescence and senescence. We will selectively disrupt RB and DREAM to assess their role in the quiescence and senescence state, E2F dependent gene expression and cell cycle entry and progression. We will identify specific RB and DREAM DNA binding sites during quiescence and senescence. We will identify histone modifications of E2F dependent genes and determine their response to selective perturbations in RB and DREAM. (2) Assess the impact of SV40 LT on RB and DREAM activity in quiescence and senescence. We will determine the specific impact of SV40 LT on cellular quiescence and senescence by expressing LT cDNA constructs that selectively interfere with RB, DREAM and p53. (3) Assess the specific contribution of novel SV40 LT-host cell interacting factors on quiescence. We will determine the specific contribution of STUB1, BAG2, DNAJC7 and HSPBP1 to SV40 LT mediated transformation and disruption of the DREAM complex. We will map their interactions with SV40 LT and determine their contribution to cellular transformation. We will assess the impact of the novel LT interacting proteins on p130 phosphorylation and stability and DREAM complex assembly and target gene expression. Significance: The goals of this proposal are to distinguish the contributions of RB and DREAM to cellular quiescence and senescence and determine their role in tumor suppression. We develop a detailed molecular profile of cellular quiescence and senescence and determine the consequences of selective RB and DREAM disruption by cellular and viral oncogenes. Achieving the goals of this proposal will address a critical barrier n our understanding of the molecular basis of quiescence and senescence and their role in tumor suppression.
Most normal cells and many cancer cells can stop proliferating and enter into a state of quiescence where they remain indefinitely until prompted by growth signals to grow again or will enter into a senescent state where they are unable to resume growth. We will determine how cells enter into quiescence and senescence and maintain their growth-arrested state. Understanding how cells maintain quiescence and senescence will provide new therapeutic opportunities to regulate the growth of normal and cancer cells.
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