Kitagawa R: Research Summary



The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation by monitoring the attachment of sister kinetochores to the bipolar mitotic spindle and preventing sister chromatid separation in the presence of unattached or tension-free kinetochores. Defects in this surveillance system cause chromosome instability (CIN) in daughter cells due to premature sister chromatid separation. One outcome of CIN is aneuploidy, which is a hallmark of many cancers. Although the frequency of mutations in known SAC genes identified in tumor cell lines which have a defect in anti-microtubule drug induced-mitotic arrest, there appears to be some correlation between sensitivity to anti-microtubule drugs and the expression level of SAC genes. Recent reverse genetics studies using mice hemizygous for SAC genes also demonstrated the causal relation between compromised SAC activity and increase in cancer susceptibility. Thus, accumulating genetic evidence strongly suggests that the deregulated or compromised SAC cause CIN and cancer. Therefore, studies of the genes that regulate SAC activity are directly relevant to research on cancer and many genetic diseases.

My research focuses on the characterization of Mad1, a conserved SAC component, and its genetic or physical interactors. Because I am particularly interested in the role of the SAC pathway in multicellular organisms during development, my laboratory is using C. elegans as a model organism in which to analyze the physiological function of the SAC components at well-defined developmental stages. Although MAD1 in budding yeast is dispensable under normal conditions and is required only for the response to defects in microtubule or kinetochore functions, CeMAD1, the C. elegans homolog of MAD1, has essential roles in maintaining the animal's viability and fertility. This finding indicates that the correct timing of SAC-regulated mitosis is a crucial aspect of C. elegans development. Investigation of the role of MAD1 in a simple multicellular organism in combination with a biochemical approach to identify the physical interactors will provide us with new insight into the physiological function of the SAC pathway that cannot be obtained from studies with monocellular systems.

My research addresses the central hypothesis that CeMAD1 is involved in the initial step of the SAC-signaling pathway and that CeMAD1 activity is regulated by multiple pathways that mediate various developmental or environmental cues. My goals are to identify and characterize proteins that regulate SAC activity in multicellular organisms and to elucidate the molecular mechanism by which SAC activity is temporally and spatially regulated during development. To this end, I have been conducting research projects as described below. I am also investigating a molecular link between DNA damage checkpoint and spindle assembly checkpoint.


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