PARK2, A Large Common Fragile Site Gene, is Part of a Stress Response Network in Normal Cells that is Disrupted During the Ovarian Cancer

摘要

PARK2 (Parkin) is a large gene spanning 1.3 megabases of genomic sequence within the unstable FRA6E (6q26) CFS. The two questions addressed here are what role the inactivation of Parkin plays in the development of ovarian cancer and whether this gene functions as part of a stress response network. First, we analyzed the effect of reintroducing Parkin into ovarian cancer cell lines lacking expression. Re-introduction of Parkin is associated with greater sensitivity to apoptotic induction. Utilizing real-time RT-PCR, we measured the expression of seven large genes residing within CFSs, including Parkin, in panels of cancer cell lines and primary tumors of the prostate, ovary, breast, brain and liver. This reveals non-random inactivation of these genes in cancers with greater inactivation of the large CFS genes in cancers that have a poorer clinical prognosis. This may offer a prognostic test of individual ovarian cancers based upon the number of large CFS genes inactivated in each cancer. Next, we examined Parkin as a stress response gene within cells. We utilized genome tiling arrays to characterize transcripts within and around Parkin and their response to two stresses. These studies reveal non-coding transcripts within large CFS genes. These studies support our overall hypothesis that the large CFS genes function as a stress response system within cells that are uniquely susceptible to genomic instability.