Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bcl-2-related anti- and proapoptotic proteins are important in the decision step of the intracellular death program upstream from the caspase proteases. Targeted overexpression of Bcl-2 in ovarian somatic cells of transgenic mice leads to decreased apoptosis of granulosa cells and is associated with higher ovulation rate, increased litter size, and ovarian teratoma formation. The ability of exogenous Bcl-2 proteins to promote follicle cell survival suggests that the transgene can bind to endogenous ovarian Bcl-2 family members and modulate the intracellular apoptosis process in favor of cell survival. We used the yeast two-hybrid system to search for ovarian Bcl-2 interacting proteins. The screening of an ovarian fusion complementary DNA library yielded several clones encoding for the death agonist Bcl-XL/Bcl-2-associated death promoter (BAD). Dimerization of Bcl-2-related proteins mediated by the consensus Bcl-2 homology (BH) domains is essential for their apoptosis-regulating function. Consistent with these observations, yeast two-hybrid assays indicated that the interaction of Bcl-2 with BAD is dependent on both BH4 and BH2 domains of Bcl-2. Northern blot analysis showed a wide distribution of BAD messenger RNA (mRNA) in diverse tissues with highest levels in the lung, ovary, uterus, and brain. In situ hybridization analysis indicated BAD mRNA expression in granulosa cells of different sizes of follicles and also in the theca and interstitial cells. BAD mRNA was expressed in the ovaries between postnatal 15-27 days and did not alter during the developmentally occurring apoptosis found about postnatal day 18 when the first group of early antral follicles were formed. Similarly, BAD mRNA levels did not change during follicle atresia induced by estrogen withdrawal in immature rats. To study the role of BAD in the ovary, BAD complementary DNA was transfected into primary cultures of granulosa cells and in a gonadal tumor cell line. Overexpression of BAD induced apoptosis in both cell types, and the effect of BAD was reversed by a membrane-permeable caspase inhibitor, indicating that BAD induces apoptosis via the activation of caspase cysteine proteases. In summary, the death agonist BAD was identified as a Bcl-2-interacting protein in the ovary, and BAD mRNA is constitutively expressed in granulosa cells, suggesting that BAD is an essential part of the ovarian cell death process. Because BAD overexpression in granulosa cells leads to apoptosis, future studies on ovarian BAD binding proteins and hormonal regulation of the interactions among different Bcl-2 family members could provide a better understanding of the cellular mechanism of ovarian follicle atresia.
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PMID:Expression and function of a proapoptotic Bcl-2 family member Bcl-XL/Bcl-2-associated death promoter (BAD) in rat ovary. 938 36

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.
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PMID:Inactivating mutations of proapoptotic Bad gene in human colon cancers. 1503 4