Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan.
Br J Cancer. 2010 Mar 16;102(6):1061-7. doi: 10.1038/sj.bjc.6605577. Epub 2010 Feb 16.
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.
DBC1/KIAA1967（乳腺癌 1 号缺失基因）是从乳腺癌标本的杂合缺失区域克隆出来的假定肿瘤抑制基因。DBC1 的半胱氨酸蛋白酶依赖性加工可促进细胞凋亡，而内源性 DBC1 的缺失通过其对 SIRT1 的特异性抑制，负调控 p53 依赖性细胞凋亡。遗传性乳腺癌和卵巢癌易感基因产物 BRCA1 通过与 SIRT1 启动子区域结合，正向调控 SIRT1 的表达。
在体内和体外研究 DBC1 与 BRCA1 之间的物理相互作用。为了确定 DBC1 的病理生理意义，研究了其作为转录因子的作用。
我们发现 DBC1 的氨基末端与 BRCA1 的羧基末端（也称为 BRCT 结构域）之间存在物理相互作用。内源性 DBC1 和 BRCA1 在完整细胞的核内形成复合物，在紫外线诱导的细胞凋亡过程中被输出到细胞质中。我们还表明，瞬时表达实验表明 DBC1 的表达抑制 BRCT 的转录激活功能。DBC1 的表达也抑制全长 BRCA1 介导的 SIRT1 启动子的转录激活。
这些结果表明 DBC1 可能调节 BRCA1 的细胞功能，并对理解乳腺组织中的癌变具有重要意义。
