Identification of DBC1 as a transcriptional repressor for BRCA1

• Published in: British journal of cancer Vol. 102; no. 6; pp. 1061 - 1067
• Main Authors: Hiraike, H, Wada-Hiraike, O, Nakagawa, S, Koyama, S, Miyamoto, Y, Sone, K, Tanikawa, M, Tsuruga, T, Nagasaka, K, Matsumoto, Y, Oda, K, Shoji, K, Fukuhara, H, Saji, S, Nakagawa, K, Kato, S, Yano, T, Taketani, Y
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 16.03.2010
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - physiology; Apoptosis; Apoptosis - genetics; BRCA1 Protein - chemistry; BRCA1 Protein - metabolism; BRCA1 Protein - physiology; Breast cancer; Cancer research; Cells, Cultured; Cloning; Gene Expression Regulation, Neoplastic; Genetics and Genomics; HeLa Cells; Humans; Medical research; Ovarian cancer; Protein Binding; Protein Structure, Tertiary - physiology; Repressor Proteins - metabolism; Repressor Proteins - physiology; Sirtuin 1 - genetics; Tissue Distribution; Transcriptional Activation - genetics; United States > US; Japan
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605577

DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumour-suppressor gene cloned from a heterozygously deleted region in breast cancer specimens. Caspase-dependent processing of DBC1 promotes apoptosis, and depletion of endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1. Hereditary breast and ovarian cancer susceptibility gene product BRCA1, by binding to the promoter region of SIRT1, is a positive regulator of SIRT1 expression. A physical interaction between DBC1 and BRCA1 was investigated both in vivo and in vitro. To determine the pathophysiological significance of DBC1, its role as a transcriptional factor was studied. We found a physical interaction between the amino terminus of DBC1 and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous DBC1 and BRCA1 form a complex in the nucleus of intact cells, which is exported to the cytoplasm during ultraviolet-induced apoptosis. We also showed that the expression of DBC1 represses the transcriptional activation function of BRCT by a transient expression assay. The expression of DBC1 also inhibits the transactivation of the SIRT1 promoter mediated by full-length BRCA1. These results revealed that DBC1 may modulate the cellular functions of BRCA1 and have important implications in the understanding of carcinogenesis in breast tissue.