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

Abstract

Abstract : PARK2 (Parkin) is an extremely large gene that spans greater than 1.3 megabases of genomic sequence within chromosomal band 6q26. This gene is derived from within the distal end of the highly unstable FRA6E (6q26) common fragile site (CFS). CFSs are large chromosomal regions that are highly unstable, found in all individuals, and prone to deletions and other aberrations, especially in developing cancer cells. The central two questions that we want to address with this work are what role does inactivation of Parkin and other large CFS genes play in the development of ovarian cancer and whether these genes function as part of a stress response network. In order to address these two questions, we have analyzed the effect of re-introducing Parkin (and several other large CFS genes) into ovarian cancer cell lines that do not express it. We have now shown that the re-introduction of Parkin, and several other CFS genes, is associated with greater sensitivity to the induction of apoptosis. This is consistent with our hypothesis that the inactivation of these genes contributes of ovarian cancer development. We have now identified 20 extremely large genes like Parkin that reside within CFS regions. To determine if these genes are randomly inactivated during cancer development, we have utilized realtime RT-PCR analysis to measure the expression of a number of these genes including Parkin in panels of cancer cell lines and primary tumors for cancers of the prostate, ovary, breast, brain and liver. This analysis reveals a decidedly non-random inactivation of the expression of these genes in different cancers. In addition, we've found that there is a greater inactivation of expression of the large CFS genes (and greater numbers of these genes inactivated) in cancers that are generally more aggressive and have a poorer overall clinical prognosis.