Novel BRCA2-interacting protein BJ-HCC-20A inhibits the induction of apoptosis in response to DNA damage.
The major hereditary breast cancer susceptibility gene BRCA2 is associated with familial breast and ovarian cancer. BRCA2 plays a role in DNA repair, transcription, cell cycle regulation, maintenance of genomic stability in response to DNA damage, centrosome regulation, and cytokinesis. To further understand the function of BRCA2, we used a yeast two-hybrid method and identified a novel BRCA2-interacting protein, BJ-HCC-20A, which is reported to be a potential cancer-testis antigen. We confirmed the interaction between endogenous BJ-HCC-20A and BRCA2 in mammalian cells, and showed that BJ-HCC-20A interacts with a portion of the highly conserved region of BRCA2 in various mammals, and M phase-specific phosphorylation of the binding region of BRCA2 modulates BJ-HCC-20A binding. Overexpression of BJ-HCC-20A increases cell growth, and downregulation of endogenous BJ-HCC-20A expression using small interfering RNA suppresses cell growth and leads to the induction of apoptosis. Importantly, the BJ-HCC-20A mRNA level is downregulated by adriamycin (ADR)-induced DNA damage and depletion of BJ-HCC-20A expression by small interfering RNA promotes the reduction of BRCA2 expression and enhances cell apoptosis in response to DNA damage. Additionally, the recovery of BJ-HCC-20A expression in ADR-induced DNA damage inhibits ADR-induced apoptosis. The data suggest that BJ-HCC-20A promotes cell growth and may regulate the induction of cell apoptosis in response to DNA damage in cooperation with BRCA2 in an M phase-dependent manner. Therefore, we speculate that targeting BJ-HCC-20A may aid in the treatment of breast tumors.
Tomiyoshi
Go
G
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-34 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Nakanishi
Akira
A
Takenaka
Katsuya
K
Yoshida
Kiyotsugu
K
Miki
Yoshio
Y
D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017124:Conserved Sequence; D004249:DNA Damage / Q000235:genetics; D015536:Down-Regulation; D004317:Doxorubicin / Q000633:toxicity; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D000097869:Polo-Like Kinase 1
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1