Centrosomes are involved in mitotic spindle organization and an increasing number of other fundamental cellular processes. Defects in centrosomes contribute to spindle defects, chromosome missegregation and aneuploidy. Recent work initially from our labraotory and one other showed that centrosome defects are a characteristic feature of human tumors. The long-term goal of our laboratory is to gain insight into the function of centrosomes and centrosome proteins in fundamental cellular processes and human cancer, toward this goal, we recently discovered that the centrosome protein pericentrin interacts with proteins of the nucleosome remodeling and deacetylase (NuRD) complex. Our preliminary results show that NuRD complex components are at the centrosome and that alteration of their levels affects centrosome integrity, spindle organization and genetic stability. We unexpectedly found that pericentrin localizes to the nucleus and that functional abrogation of pericentrin has dramatic effects on nuclear structure. We have also shown that pericentrin induces the formation of multipolar spindles when elevated in cells and mislocalizes dynein from spindles. Other work confirms that loss of dynein from mitotic spindles induces multipolarity and shows that re-establishing dynein binding to spindles results in clustering of spindle poles and restoration of spindle bipority. Based on these observations we propose three specific aims:
Aim 1. To determine the mechanism of centrosome disruption and spindle dysfunction in cells with abrogated NuRD components.
Aim 2. To determine the mechanism of nuclear disruption and functional changes in nuclei following abrogation of pericentrin function.
Aim 3. To restore spindle bipolarity in tumor cells that have multipolar spindles and elevated levels of pericentrin as was accomplished in tumor cells overexpressing another dynein-interacting protein, NuMA. If successful this work will increase our basic understanding of centrosomes and centrosome proteins. In addition, it will provide information on how cells develop genetic changes that accompany human tumorigenesis. This could prove useful in cancer diagnosis and prognosis, and provide new targets for designing cancer therapeutics.
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