Building Breast Cancer: Dissecting the Contribution of Pericentrin and its Binding Partners to Chromosome Instability and Tumorigenesis
Abstract
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2004
- Accession Number
- ADA426156
Entities
People
- Keith W. Mikule
Organizations
- University of Massachusetts