The accurate transmission of genetic information during the cell cycle is dependent on the correct operation of a spindle assembly checkpoint the monitors the state of chromosome-microtubule attachment. Signals generated at kinetochores and transmitted via a transduction system comprised of Mad and Bub proteins, act to regulate the activity of the anaphase promoting complex (APC) thereby linking cell cycle progression to the correct execution of the mechanical events of mitosis. The goal of this work is to probe the mechanisms of checkpoint gene activation with the goal of defining the upstream events that initiate checkpoint signaling and the downstream events that control APC. In addition, the role played by checkpoint lesions in genomic instability in mice will be examined through the use of conditional alleles in two checkpoint genes. Specifically: (1) The mechanism by which p53-loss rescues the viability of cells lacking a spindle checkpoint will be analyzed in vitro and in vivo (2) The mechanism of action of a recently discovered negative regulator of Mad2 (CMT2) will be analyzed in detail to uncover key aspects of Mad2-mediated checkpoint signaling. (3) The proteins responsible for recruiting Mad and Bub proteins to kinetochores will be studied, with particular emphasis on the members of the Ndc80 complex (4) Bub1, a kinase with dual functions in checkpoint control and chromosome-microtubule attachment will be analyzed using specific mutations that abrogate various functions (5) The potential role of checkpoint lesions in generating chromosome instability and in promoting cancer will be examined in mice using conditional alleles and mouse model off lung cancer development. The molecular analysis of checkpoints will have an impact on two aspects of cancer biology. First, it should help to reveal the mechanism off action of important anti-microtubule chemotherapeutics such as taxol and the vinca alkaloids. These compounds provoke the spindle checkpoint, and lesions in the checkpoint are very likely to alter the effectiveness of these drugs in the clinic. Second, careful study of the spindle checkpoint should clarify the role of chromosome instability on tumor development.
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