Dual role of proapoptotic BAD in insulin secretion and beta cell survival

被引：248

作者：

Danial, Nika N. ^{[1
,3
,4
]}

Walensky, Loren D. ^{[2
,3
,4
,5
]}

Zhang, Chen-Yu ^{[6
]}

Choi, Cheol Soo ^{[7
,8
]}

Fisher, Jill K. ^{[1
,3
,4
]}

Molina, Anthony J. A. ^{[9
]}

Datta, Sandeep Robert ^{[10
]}

Pitter, Kenneth L. ^{[2
,3
,4
,5
]}

Bird, Gregory H. ^{[2
,3
,4
,5
]}

Wikstrom, Jakob D. ^{[9
]}

Deeney, Jude T. ^{[11
]}

Robertson, Kirsten ^{[1
,3
,4
]}

Morash, Joel ^{[2
,3
,4
,5
]}

Kulkarni, Ameya ^{[7
,8
]}

Neschen, Susanne ^{[7
,8
]}

Kim, Sheene ^{[7
,8
]}

Greenberg, Michael E. ^{[10
]}

Corkey, Barbara E. ^{[11
]}

Shirihai, Orian S. ^{[9
]}

Shulman, Gerald I. ^{[7
,8
]}

Lowell, Bradford B. ^{[1
,12
]}

Korsmeyer, Stanley J. ^{[1
,7
]}

机构：

[1] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA

[5] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[6] Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing 210093, Peoples R China

[7] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA

[8] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA

[9] Tufts Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02111 USA

[10] Childrens Hosp, Dept Neurol, Neurobiol Program, Boston, MA 02115 USA

[11] Boston Univ, Med Ctr, Evans Dept Med, Obes Res Ctr, Boston, MA 02118 USA

[12] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Div Endocrionol, Boston, MA 02215 USA

来源：

NATURE MEDICINE | 2008年 / 14卷 / 02期

关键词：

D O I：

10.1038/nm1717

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion.

引用

页码：144 / 153

页数：10

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