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

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

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.

Citation

Yuan, T., Rafizadeh, S., Azizi, Z., Lupse, B., Devi Gorrepati, K. D., Awal, S., Oberholzer, J., Maedler, K., & Ardestani, A. (2016). Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic β cells. JCI Insight, 1(18), Article e86326. https://doi.org/10.1172/jci.insight.86326

• Journal Article Type: Article
• Acceptance Date: Oct 5, 2016
• Online Publication Date: Nov 3, 2016
• Publication Date: Nov 3, 2016
• Deposit Date: Jan 4, 2024
• Journal: JCI Insight
• Electronic ISSN: 2379-3708
• Publisher: American Society for Clinical Investigation
• Peer Reviewed: Peer Reviewed
• Volume: 1
• Issue: 18
• Article Number: e86326
• DOI: https://doi.org/10.1172/jci.insight.86326
• Public URL: https://hull-repository.worktribe.com/output/4461676