Role of the XIAP/AIF Axis in the Development and Progression of Prostate Cancer
Abstract
Over the project period, significant progress was made towards completing the tasks outlined in the original Statement of Work. The physical association between XIAP and AIF was confirmed in living cells, and was determined to be highly dependant upon the ubiquitination status of AIF. This interaction could be disrupted by Smac/DIABLO, in a manner that correlated with AIF ubiquitination. AIF was shown to be a substrate for XIAP-mediated ubiquitination, which did not result in AIF degradation. The caspase inhibitory properties of XIAP were found to be insensitive to AIF expression and dispensable for AIF binding. AIF overexpression resulted in significant increases in cellular reactive oxygen species levels that were not attenuated by co- expression of XIAP. It was shown that the XIAP antagonist and serine protease Omi/HtrA2 was capable of cleaving AIF, yet the loss of Omi/HtrA2 did not affect the cytoplasmic release of AIF during apoptosis. Finally, AIF was found to associate with the XIAP homologues cIAP-I and cIAP-2, suggesting that AIF may be a general purpose lAP binding protein. Taken together, these findings not only confirm the physiological relevance of the association between XlAP and AIF, but also establish a functional link between XIAP and AIF, and form the basis for understanding how these two molecules contribute to the development and progression of prostate cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2007
- Accession Number
- ADA472756
Entities
People
- John C. Wilkinson
Organizations
- University of Michigan