Differential Regulation of Expression of ER Stress Proteins by BRCA1 during Ovarian Follicular Development
Elena Enbom, Ying Liu, Amy Lee, Louis Dubeau. University of Southern California, Los Angeles, CA; Harbor-UCLA, Torrance, CA
Background: Expressions of glucose-regulated protein (GRP) 78, a critical regulator of the unfolded protein response (UPR), and of GRP94, an important component of UPR, are often inversely related to expression of BRCA1 a protein associated with familial ovarian cancer predisposition. GRP78 and GRP94 are known to be highly expressed in normal ovaries.
Design: We sought to investigate their source and distribution of expression in this organ and to test the hypothesis that their expression is controlled by BRCA1. This entailed immunochemical examinations using antibodies against GRP78, GRP94, Brca1, and markers of UPR stress such as CHOP, PDI, peIF2 and eIF2 in mouse ovaries at different stages of development using a mouse model characterized by conditional inactivation of Brca1 in ovarian in ovarian granulosa cells.
Results: The results showed high levels of expression of both GRP78 and GRP94 in primordial follicular cells and in ovarian granulosa cells of developing and mature ovarian follicles.
GRP94 expression was also elevated in oocytes of primary and secondary follicles, but not of primordial follicles. Within secondary follicles, the distribution of GRP78/GRP94 was decreased in the peri-oocyte area, the predominant area of Brca1 expression. Inactivation of Brca1 resulted in uniform expression of GRP78/GRP94 throughout the follicles, including in the peri-oocyte area. Examination of the distribution of expression of UPR stress markers in wild type and Brca1 mutant mice showed that inactivation of BRCA1 leads to elevation of CHOP, decrease of PDI and peIF2 with unchanged total eIF2.
Conclusions: We conclude that primordial ovarian follicular cells at all stage of development are the main source of GRP78/GRP94 in mouse ovaries. GRP94 is also expressed in oocytes only in ovarian follicles that have developed further than the primordial follicular stage. Expression of GRP78 and GRP94 are inversely related to expression of Brca1 in ovarian follicles. Inactivation of Brca1 not only leads to increased expression of GRP78/GRP94 in granulosa cells surrounding the oocytes within developing follicles, but also to induction of ER stress due to unfolded protein response.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 281, Monday Morning