Centrosomes are multifunctional organelles crucial for a large number of cellular functions including the organization of microtubules. In mitosis centrosomes contribute to assembly, orientation and function of the mitotic spindle, which is important for proper segregation of the chromosomes. Defects in centrosome number and function are strongly associated with the cancer phenotype and centrosomes offer potential new targets for anti-mitotic cancer drugs. Recent data suggests that microtubule organization at centrosomes also has implications for aspects of cellular differentiation, and that several human genetic diseases can be linked to centrosome malfunction. The characterization of proteins required for the function of the centrosome as a microtubule organizing center (MTOC) might reveal how structural and functional centrosome aberrations affect genomic stability and cancer development as well as developmental processes. I will study a key component of the centrosome and other MTOCs, the gamma-tubulin complex, and identify and characterize additional centrosome proteins involved in microtubule organization. I propose to: 1) analyze the mitosis-specific function and regulation of gamma-tubulin and associated proteins, 2) reconstitute the centrosomal attachment and function of the gamma-tubulin complex in a purified system in vitro, and 3) test proteins of the centrosome proteome for localization to a non-centrosomal microtubule organizing center, to identify and characterize those centrosome proteins specifically involved in microtubule organization.
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