Proproliferative and Antiapoptotic Action of Exogenously Introduced YAP in Pancreatic β Cells

JCI Insight. 2016 Nov 3;1(18):e86326. doi: 10.1172/jci.insight.86326.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Apoptosis*
  • Cell Line
  • Cell Proliferation*
  • Forkhead Box Protein M1 / metabolism
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Phosphoproteins / genetics*
  • Rats
  • Signal Transduction
  • Thioredoxins / metabolism
  • Transcription Factors / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Phosphoproteins
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Thioredoxins