Noncanonical CDK4 signaling rescues diabetes in a mouse model by promoting β cell differentiation

被引:1
|
作者
Stamateris, Rachel E. [1 ]
Landa-Galvan, Huguet V. [2 ,3 ]
Sharma, Rohit B. [2 ,3 ]
Darko, Christine [2 ,3 ]
Redmond, David [4 ]
Rane, Sushil G. [5 ]
Alonso, Laura C. [2 ,3 ]
机构
[1] Univ Massachusetts Med Sch, MD PhD Program, Sch Med, Worcester, MA USA
[2] Weill Cornell Med, Div Endocrinol Diabet & Metab, New York, NY USA
[3] Weill Cornell Med, Joan & Sanford I Weill Ctr Metab Hlth, New York, NY USA
[4] Weill Cornell Med, Hartman Inst Therapeut Regenerat Med, Div Regenerat Med, Dept Med, New York, NY USA
[5] Natl Inst Diabet Digest & Kidney Dis, Integrat Cellular Metab Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA
来源
JOURNAL OF CLINICAL INVESTIGATION | 2023年 / 133卷 / 18期
关键词
TRANSCRIPTION FACTOR FOXO1; GENE-EXPRESSION; INSULIN-RESISTANCE; CYCLIN D2; GLY1057ASP POLYMORPHISM; NUCLEAR EXPORT; PHOSPHORYLATION; PROLIFERATION; PROTEIN; MICE;
D O I
10.1172/JCI166490
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Expanding beta cell mass is a critical goal in the fight against diabetes. CDK4, an extensively characterized cell cycle activator, is required to establish and maintain beta cell number. beta cell failure in the IRS2-deletion mouse type 2 diabetes model is, in part, due to loss of CDK4 regulator cyclin D2. We set out to determine whether replacement of endogenous CDK4 with the inhibitor-resistant mutant CDK4-R24C rescued the loss of beta cell mass in IRS2-deficient mice. Surprisingly, not only beta cell mass but also beta cell dedifferentiation was effectively rescued, despite no improvement in whole body insulin sensitivity. Ex vivo studies in primary islet cells revealed a mechanism in which CDK4 intervened downstream in the insulin signaling pathway to prevent FOXO1-mediated transcriptional repression of critical beta cell transcription factor Pdx1. FOXO1 inhibition was not related to E2F1 activity, to FOXO1 phosphorylation, or even to FOXO1 subcellular localization, but rather was related to deacetylation and reduced FOXO1 abundance. Taken together, these results demonstrate a differentiation-promoting activity of the classical cell cycle activator CDK4 and support the concept that beta cell mass can be expanded without compromising function.
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页数:15
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