BRCA2 suppresses cell proliferation via stabilizing MAGE-D1.
Germ line mutations in BRCA2 gene predispose women to early-onset familial breast and ovarian cancer. BRCA2 is a protein of multiple functions. In addition to its role in DNA double-strand break repair, BRCA2 also plays a role in stabilization of stalled DNA replication forks, cytokinesis, transcription regulation, mammalian gametogenesis, centrosome duplication, and suppression of cell proliferation. However, how BRCA2 mutations predispose women specifically to breast and ovarian cancer remains undefined. Here we found that BRCA2 binds and stabilizes MAGE-D1, a member of the MAGE gene family of proteins. Expression of BRCA2 and MAGE-D1 synergistically suppresses cell proliferation independently of the p53 pathway. Using two MAGE-D1 RNA interferences and two cell lines expressing low or undetectable levels of MAGE-D1, we further showed that the expression of MAGE-D1 is required for BRCA2-mediated suppression of cell proliferation, indicating that MAGE-D1 is a downstream target of BRCA2 and that BRCA2 suppresses cell proliferation via stabilizing MAGE-D1. Importantly, MAGE-D1 protein expression was reduced in 6 of 16 breast carcinoma cell lines tested as compared with untransformed immortal mammary epithelial cell lines, suggesting that suppression of MAGE-D1 expression may be involved in the tumorigenesis of a subset of sporadic breast cancers.
Tian
Xin-xia
XX
Division of Cancer Biology, Evanston Northwestern Healthcare Research Institute, Department of Medicine, Northwestern University Feinberg School of Medicine, Evanston, Illinois 60201, USA.
Rai
Deepak
D
Li
Jun
J
Zou
Chaozhong
C
Bai
Yujie
Y
Wazer
David
D
Band
Vimla
V
Gao
Qingshen
Q
D000951:Antigens, Neoplasm; D024682:BRCA2 Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism*; D011485:Protein Binding; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000951:Antigens, Neoplasm; D024682:BRCA2 Protein; C120897:MAGED1 protein, human; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53