Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreaticβcells.
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.
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Ting
T
Yuan
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Sahar
S
Rafizadeh
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Zahra
Z
Azizi
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Blaz
B
Lupse
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Kanaka Durga Devi
KDD
Gorrepati
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Sushil
S
Awal
Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois, USA.
Jose
J
Oberholzer
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.|German Center for Diabetes Research (DZD) project partner, University of Bremen, Bremen, Germany.
Kathrin
K
Maedler
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Amin
A
Ardestani
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D000072278:Forkhead Box Protein M1 / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology*; D010750:Phosphoproteins / Q000235:genetics*; D051381:Rats; D015398:Signal Transduction; D013879:Thioredoxins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D013879:Thioredoxins