Building Breast Cancer: Dissecting the Contribution of Pericentrin and its Binding Partners to Chromosome Instability and Tumorigenesis
Annual Summary rept. 1 May 2003-30 Apr 2004
MASSACHUSETTS UNIV MEDICAL CENTER WORCESTER
Pagination or Media Count:
Breast tumors are aneuploid and contain high pericentrin levels. The ABC kinases, known individually as protein kinases A, B akt, and C have each been linked to breast carcinogenesis. Pericentrin has binding sites for ABC kinases and may be a scaffold for their centrosome localization. Since pericentrin expression in vitro causes aneuploidy, it 5 intriguing to suggest that pericentrin is an oncogene whose oncogenic potential binges upon its association with one or more ABC kinases. To address this, we asked if endogenous pericentrin binds ABC kinases in-vivo, and whether disruption of pericentrin- kinase interactions would cause aneuploidy. We found that pericentrin binds all three kinases and that disruption of PKC and PKA from the centrosome causes aneupoidy as a result of cytokinetic failure and microtubule disorganization, consistent with these kinases playing a role in tumorigenesis. Overexpression of Akt also results in the production of binucleate cells. Additionally, we discovered active IKK complex-also linked to breast carcinogenesis, at the centrosome and found that it functions in centrosome duplication and cytokinesis aneuploidy. Perhaps most surprisingly, we have identified a centrosome damage G1 checkpoint that is dependent upon intect p53 and p38 signaling. Each of these discoveries has important implications for breast tumor biology.
- Medicine and Medical Research