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• W2166880430 abstract "BackgroundPancreatic beta cell apoptosis promotes progressive beta cell dysfunction and has been implicated as a causal factor in the development of diabetes. Since BRCA1 is known to regulate DNA damage repair and afford cellular resistance against apoptosis, we hypothesized that it may serve as a previously unrecognized target to limit pancreatic beta cell apoptosis and improve beta cell function.Methods/ResultsHuman pancreatic beta cells were studied in culture either under basal conditions or in the presence of genotoxic stress induced by doxorubicin. Beta cell apoptosis, as evaluated by pro-caspase-3 cleavage, the TUNEL assay, DNA-laddering and co-staining with Annexin V-FITC and propidium iodide, was increased by doxorubicin (0-10 μm) in a concentration-dependent manner. Assessment of ãH2AX levels revealed impairment of beta cell double strand DNA damage repair by doxorubicin. Doxorubicin treatment also elevated beta cell expression of the tumor suppressor and master pro-apoptotic molecule p53. Importantly, in gain-of-function studies, adenoviral over-expression of BRCA1 (Ad-BRCA1) was associated with marked attenuation of doxorubicin-elicited pancreatic beta cell apoptosis, restoration of double strand DNA damage repair, and attenuated increases of p53 levels evoked by doxorubicin, all consistent with a protective effect against genotoxic stress-induced beta cell injury. Of further note, relative to beta cells that had been treated with the adeno-CMV-null vector prior to stimulation with doxorubicin, beta cells that were transfected with Ad-BRCA1 before doxorubicin treatment were afforded protection against progressive loss of insulin secretion.ConclusionWe report an entirely novel role of BRCA1 as a cellular target to limit pancreatic beta cell apoptosis and beta cell dysfunction in response to genotoxic stimulation with doxorubicin. These observations require in vivo validation and translation in animal models of diabetes. BackgroundPancreatic beta cell apoptosis promotes progressive beta cell dysfunction and has been implicated as a causal factor in the development of diabetes. Since BRCA1 is known to regulate DNA damage repair and afford cellular resistance against apoptosis, we hypothesized that it may serve as a previously unrecognized target to limit pancreatic beta cell apoptosis and improve beta cell function. Pancreatic beta cell apoptosis promotes progressive beta cell dysfunction and has been implicated as a causal factor in the development of diabetes. Since BRCA1 is known to regulate DNA damage repair and afford cellular resistance against apoptosis, we hypothesized that it may serve as a previously unrecognized target to limit pancreatic beta cell apoptosis and improve beta cell function. Methods/ResultsHuman pancreatic beta cells were studied in culture either under basal conditions or in the presence of genotoxic stress induced by doxorubicin. Beta cell apoptosis, as evaluated by pro-caspase-3 cleavage, the TUNEL assay, DNA-laddering and co-staining with Annexin V-FITC and propidium iodide, was increased by doxorubicin (0-10 μm) in a concentration-dependent manner. Assessment of ãH2AX levels revealed impairment of beta cell double strand DNA damage repair by doxorubicin. Doxorubicin treatment also elevated beta cell expression of the tumor suppressor and master pro-apoptotic molecule p53. Importantly, in gain-of-function studies, adenoviral over-expression of BRCA1 (Ad-BRCA1) was associated with marked attenuation of doxorubicin-elicited pancreatic beta cell apoptosis, restoration of double strand DNA damage repair, and attenuated increases of p53 levels evoked by doxorubicin, all consistent with a protective effect against genotoxic stress-induced beta cell injury. Of further note, relative to beta cells that had been treated with the adeno-CMV-null vector prior to stimulation with doxorubicin, beta cells that were transfected with Ad-BRCA1 before doxorubicin treatment were afforded protection against progressive loss of insulin secretion. Human pancreatic beta cells were studied in culture either under basal conditions or in the presence of genotoxic stress induced by doxorubicin. Beta cell apoptosis, as evaluated by pro-caspase-3 cleavage, the TUNEL assay, DNA-laddering and co-staining with Annexin V-FITC and propidium iodide, was increased by doxorubicin (0-10 μm) in a concentration-dependent manner. Assessment of ãH2AX levels revealed impairment of beta cell double strand DNA damage repair by doxorubicin. Doxorubicin treatment also elevated beta cell expression of the tumor suppressor and master pro-apoptotic molecule p53. Importantly, in gain-of-function studies, adenoviral over-expression of BRCA1 (Ad-BRCA1) was associated with marked attenuation of doxorubicin-elicited pancreatic beta cell apoptosis, restoration of double strand DNA damage repair, and attenuated increases of p53 levels evoked by doxorubicin, all consistent with a protective effect against genotoxic stress-induced beta cell injury. Of further note, relative to beta cells that had been treated with the adeno-CMV-null vector prior to stimulation with doxorubicin, beta cells that were transfected with Ad-BRCA1 before doxorubicin treatment were afforded protection against progressive loss of insulin secretion. ConclusionWe report an entirely novel role of BRCA1 as a cellular target to limit pancreatic beta cell apoptosis and beta cell dysfunction in response to genotoxic stimulation with doxorubicin. These observations require in vivo validation and translation in animal models of diabetes. We report an entirely novel role of BRCA1 as a cellular target to limit pancreatic beta cell apoptosis and beta cell dysfunction in response to genotoxic stimulation with doxorubicin. These observations require in vivo validation and translation in animal models of diabetes." @default.
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• W2166880430 date "2012-09-01" @default.
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• W2166880430 title "530 BRCA1 is a Novel Molecular Target to Limit Pancreatic Beta Cell Apoptosis and Restore Beta Cell Function" @default.
• W2166880430 doi "https://doi.org/10.1016/j.cjca.2012.07.483" @default.
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