PARK2, a Large Common Fragile Site Gene, is Part of a Stress Response Network in Normal Cells that is Disrupted During the Development of Ovarian Cancer
Annual rept. 15 Dec 2003-14 Dec 2004
MAYO CLINIC ROCHESTER MN
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PARK2 Parkin is an extremely large gene that spans greater than 1.3 megabases of genomic sequence within chromosomal band 6q26. This gene is also derived from within the middle of the highly unstable FRA6E common fragile site CFS. CFSs are large chromosomal regions that are highly unstable and prone to deletions and other alterations, especially in developing cancer cells. The central two questions that we want to address with this work are what role does the inactivation of Parkin play in the development of ovarian cancer and whether this gene functions as part of a stress response network. In order to address these two questions, we have analyzed the effect of reintroducing Parkin into ovarian cancer cell lines that do not express it. We then demonstrate that the re-introduction of Parkin is associated with greater sensitivity to the induction of apoptosis. This is consistent with our hypothesis that inactivation of this gene contributes to ovarian cancer development. In order to study whether Parkin is part of a stress response network, we have begun to characterize other proteins that Parkin interacts with, including another large CFS gene WWOX. WWOX functions as part of a stress response network and is specifically phosphorylated in stressed cells and then it binds to p53, translocates to the mitochondria and induces apoptosis. We demonstrate specific interactions between Parkin and WWOX, thus Parkin may also be part of a stress response network in normal cells that is disrupted during the development of ovarian cancer.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research