Inactivating mutation of the pro-apoptotic gene BID in gastric cancer |
| |
Authors: | Lee Jong Heun Soung Young Hwa Lee Jong Woo Park Won Sang Kim Su Young Cho Yong Gu Kim Chang Jae Seo Si Hyung Kim Hong Sug Nam Suk Woo Yoo Nam Jin Lee Sug Hyung Lee Jung Young |
| |
Affiliation: | Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea. stingray@catholic.ac.kr |
| |
Abstract: | There is evidence that deregulation of apoptosis is mechanistically involved in cancer development and somatic mutations of apoptosis-related genes have been reported in human cancers. BID, a pro-apoptotic member of the Bcl-2 family, interconnects the extrinsic apoptosis pathway initiated by death receptors to the intrinsic apoptosis pathway. To explore the possibility that genetic alterations of BID might be involved in the development of human cancers, this study analysed the entire coding region and all splice sites in the human BID gene in 67 advanced gastric carcinomas. Overall, four BID mutations (6.0%) were detected that consisted of one frameshift and three missense mutations. The tumour-derived BID mutants were expressed in 293T cells and it was found that, compared with wild-type BID, the frequency of apoptosis was significantly reduced in cells expressing the gene containing the frameshift mutation. Furthermore, expression of the inactivating frameshift mutant interfered with cell death by overexpression of death receptors, indicating that this mutant inhibits the extrinsic apoptosis pathway in a dominant-negative fashion. Also, the frameshift mutation rendered cancer cells resistant to apoptosis induced by the anti-cancer drug 5-fluorouracil (5-FU). This is the first report of BID gene mutation in human malignancy. The data suggest that such mutations occur rarely in gastric cancers and that only a small fraction of BID mutations may lead to the loss of its apoptotic function. |
| |
Keywords: | BID mutation gastric cancer apoptosis |
本文献已被 PubMed 等数据库收录! |
|