Carcinogenesis Advance Access published online on March 19, 2004
Carcinogenesis, doi:10.1093/carcin/bgh145
© 2004 by Oxford University Press
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CANCER BIOLOGY
1 Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
* Corresponding author. E-mail: t5379392{at}kornet.net.
Received 12 December 2003
; revised 12 February 2004
; accepted 7 March 2004
Evidence exists that deregulation of apoptosis is involved in the mechanisms of cancer development, and the somatic mutations of apoptosis-related genes have been reported in human cancers. Bcl- XL/Bcl-2 -associated death promoter (Bad), a proapoptotic member of Bcl-2 family, plays an important role in the intrinsic apoptosis pathway. To explore the possibility that the genetic alterations of Bad might be involved in the development of human cancers, we analyzed the entire coding region and all splice sites of human Bad gene in 47 colon adenocarcinomas. Overall, we detected two somatic missense mutations (4.3%) in Bad gene. Interestingly, both of the Bad mutations were detected in the gene sequences encoding the Bcl-2 homology3 (BH3) domain of Bad, which has a crucial role in inducing cell death. Transfection study revealed that both of the tumor-derived Bad mutants had decreased apoptosis activities compared to the wild-type Bad, indicating that the Bad mutations reduced the cell death function of Bad. Co-immunoprecipitation assay revealed that binding of one of the tumor-derived Bad mutant with Bcl-2 and Bcl-XL is reduced. This is the first report on Bad gene mutation in human malignancies, and our data suggest that Bad gene is occasionally mutated in colon cancers and that somatic mutation of Bad may contribute to the development of colon cancers.
Inactivating mutations of proapoptotic Bad gene in human colon cancers
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