title: Inactivating mutations of proapoptotic Bad gene in human colon cancers.
abstract: 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 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 with 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 mutants 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.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea.
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Young Hwa
authors.initials: YH
authors.lastname: Soung
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
authors.forename: Chang Jae
authors.initials: CJ
authors.lastname: Kim
authors.forename: Yong Gu
authors.initials: YG
authors.lastname: Cho
authors.forename: Jong Heun
authors.initials: JH
authors.lastname: Lee
authors.forename: Hong Sug
authors.initials: HS
authors.lastname: Kim
authors.forename: Won Sang
authors.initials: WS
authors.lastname: Park
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Nam Jin
authors.initials: NJ
authors.lastname: Yoo
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D010957:Plasmids / Q000378:metabolism; D018807:Polymorphism, Single-Stranded Conformational; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014162:Transfection; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
chemical_list: C494819:BAD protein, human; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein