作者
Nika N Danial, Loren D Walensky, Chen-Yu Zhang, Cheol Soo Choi, Jill K Fisher, Anthony JA Molina, Sandeep Robert Datta, Kenneth L Pitter, Gregory H Bird, Jakob D Wikstrom, Jude T Deeney, Kirsten Robertson, Joel Morash, Ameya Kulkarni, Susanne Neschen, Sheene Kim, Michael E Greenberg, Barbara E Corkey, Orian S Shirihai, Gerald I Shulman, Bradford B Lowell, Stanley J Korsmeyer
发表日期
2008/2
期刊
Nature medicine
卷号
14
期号
2
页码范围
144-153
出版商
Nature Publishing Group US
简介
The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD …
引用总数
学术搜索中的文章
NN Danial, LD Walensky, CY Zhang, CS Choi… - Nature medicine, 2008