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Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic β cells
Ting Yuan, … , Kathrin Maedler, Amin Ardestani
Ting Yuan, … , Kathrin Maedler, Amin Ardestani
Published November 3, 2016
Citation Information: JCI Insight. 2016;1(18):e86326. https://doi.org/10.1172/jci.insight.86326.
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Research Article Cell biology Endocrinology

Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic β cells

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Abstract

Loss of functional pancreatic β cells is a hallmark of both type 1 and 2 diabetes. Identifying the pathways that promote β cell proliferation and/or block β cell apoptosis is a potential strategy for diabetes therapy. The transcriptional coactivator Yes-associated protein (YAP), a major downstream effector of the Hippo signaling pathway, is a key regulator of organ size and tissue homeostasis by modulating cell proliferation and apoptosis. YAP is not expressed in mature primary human and mouse β cells. We aimed to identify whether reexpression of a constitutively active form of YAP promotes β cell proliferation/survival. Overexpression of YAP remarkably induced β cell proliferation in isolated human islets, while β cell function and functional identity genes were fully preserved. The transcription factor forkhead box M1 (FOXM1) was upregulated upon YAP overexpression and necessary for YAP-dependent β cell proliferation. YAP overexpression protected β cells from apoptosis triggered by multiple diabetic conditions. The small redox proteins thioredoxin-1 and thioredoxin-2 (Trx1/2) were upregulated by YAP; disruption of the Trx system revealed that Trx1/2 was required for the antiapoptotic action of YAP in insulin-producing β cells. Our data show the robust proproliferative and antiapoptotic function of YAP in pancreatic β cells. YAP reconstitution may represent a disease-modifying approach to restore a functional β cell mass in diabetes.

Authors

Ting Yuan, Sahar Rafizadeh, Zahra Azizi, Blaz Lupse, Kanaka Durga Devi Gorrepati, Sushil Awal, Jose Oberholzer, Kathrin Maedler, Amin Ardestani

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Figure 1

YAP overexpression promotes human β cell proliferation.

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YAP overexpression promotes human β cell proliferation.
(A–D) Human isle...
(A–D) Human islets were infected with either control adenovirus expressing luciferase (Ad-Luc) or Ad-YAP for 2 days. β Cell proliferation was analyzed by double staining for Ki67 (A and B) or BrdU (C and D) (red) and insulin (green). Pooled data from 7 (A, n = 7) or 5 (C, n = 5) different human islet donors. Scale bars: 100 μm. Data are the mean ± SEM. *P < 0.001, **P < 0.01 for Ad-YAP– compared with Ad-Luc–infected islets by 2-tailed Student’s t test.
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