CENTROSOME-NUCLEAR LINKS AND CANCER

Univ Of Massachusetts Med Sch Worcester, Worcester MA

Investigators

Linked publications & trials

Abstract

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