Glucose-regulated protein 78 as a novel effector of BRCA1 for inhibiting stress-induced apoptosis.
The tumor suppressor BRCA1 is mutated in a high percentage of familial breast and ovarian cancer, but our understanding of its mechanisms of action remains incomplete. We report here that glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression. Knockdown of BRCA1 also led to induction of other components of UPR, such as GRP94 and CHOP. Consistent with a role of BRCA1 knockdown in mediating cell survival, forced expression of GRP78 stimulated cell proliferation and prevented apoptosis, including that induced by endoplasmic reticulum stress and chemotherapy, in ovarian OVCAR-3 and breast MCF-7 cancer cells. Overexpression of wild-type BRCA1 could increase the apoptosis of GRP78-overexpressing cells. Conversely, knockdown GRP78 by siRNA sensitized ovarian and breast cancer cells to apoptosis. This effect was reduced when the expression of BRCA1 was simultaneously knockdown by siRNA, indicating that BRCA1 also negatively regulates GRP78-mediated cell survival and resistance to apoptosis.
Yeung
B H Y
BH
School of Biological Sciences, University of Hong Kong, Hong Kong, China.
Kwan
B W Y
BW
He
Q Y
QY
Lee
A S
AS
Liu
J
J
Wong
A S T
AS
D017209:Apoptosis / Q000235:genetics; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D018832:Molecular Chaperones / Q000096:biosynthesis*; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000235:genetics; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP