Inactivating mutation of the pro-apoptotic gene BID in gastric cancer.
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.
Lee
Jong Heun
JH
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea. stingray@catholic.ac.kr
Soung
Young Hwa
YH
Lee
Jong Woo
JW
Park
Won Sang
WS
Kim
Su Young
SY
Cho
Yong Gu
YG
Kim
Chang Jae
CJ
Seo
Si Hyung
SH
Kim
Hong Sug
HS
Nam
Suk Woo
SW
Yoo
Nam Jin
NJ
Lee
Sug Hyung
SH
Lee
Jung Young
JY
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D042282:Microdissection; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014162:Transfection
D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D009363:Neoplasm Proteins; D005472:Fluorouracil