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Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic ? cells.

ABSTRACT: Loss of functional pancreatic ? cells is a hallmark of both type 1 and 2 diabetes. Identifying the pathways that promote ? cell proliferation and/or block ? 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 ? cells. We aimed to identify whether reexpression of a constitutively active form of YAP promotes ? cell proliferation/survival. Overexpression of YAP remarkably induced ? cell proliferation in isolated human islets, while ? 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 ? cell proliferation. YAP overexpression protected ? 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 ? cells. Our data show the robust proproliferative and antiapoptotic function of YAP in pancreatic ? cells. YAP reconstitution may represent a disease-modifying approach to restore a functional ? cell mass in diabetes.

SUBMITTER: Yuan T

PROVIDER: S-EPMC5085606 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic <b>β</b> cells.

Yuan Ting T Rafizadeh Sahar S Azizi Zahra Z Lupse Blaz B Gorrepati Kanaka Durga Devi KDD Awal Sushil S Oberholzer Jose J Maedler Kathrin K Ardestani Amin A

JCI insight 20161103 18

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 ...[more]

PMID: 27812538

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Project description:The ectopic expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR) in the human adrenal gland causes significant hypercortisolemia after ingestion of each meal and leads to Cushing's syndrome, implying that human GIPR activation is capable of robustly activating adrenal glucocorticoid secretion. In this study, we transiently transfected the human GIPR expression vector into cultured human adrenocortical carcinoma cells (H295R) and treated them with GIP to examine the direct link between GIPR activation and steroidogenesis. Using quantitative RT-PCR assay, we examined gene expression of steroidogenic related proteins, and carried out immunofluorescence analysis to prove that forced GIPR overexpression directly promotes production of steroidogenic enzymes CYP17A1 and CYP21A2 at the single cell level. Immunofluorescence showed that the transfection efficiency of the GIPR gene in H295R cells was approximately 5%, and GIP stimulation enhanced CYP21A2 and CYP17A1 expression in GIPR-introduced H295R cells (H295R-GIPR). Interestingly, these steroidogenic enzymes were also expressed in the GIPR (-) cells adjacent to the GIPR (+) cells. The mRNA levels of a cholesterol transport protein required for all steroidogenesis, StAR, and steroidogenic enzymes, HSD3?2, CYP11A1, CYP21A2, and CYP17A1 increased 1.2-2.1-fold in GIP-stimulated H295R-GIPR cells. These changes were reflected in the culture medium in which 1.5-fold increase in the cortisol concentration was confirmed. Furthermore, the levels of adenocorticotropic hormone (ACTH) receptor and ACTH precursor proopiomelanocortin (POMC) mRNA were upregulated 2- and 1.5-fold, respectively. Immunofluorescence showed that ACTH expression was detected in GIP-stimulated H295R-GIPR cells. An ACTH-receptor antagonist significantly inhibited steroidogenic gene expression and cortisol production. Immunostaining for both CYP17A1 and CYP21A2 was attenuated in cells treated with ACTH receptor antagonists as well as with POMC siRNA. These results demonstrated that GIPR activation promoted production and release of ACTH, and that steroidogenesis is activated by endogenously secreted ACTH following GIP administration, at least in part, in H295R cells.

Dataset Information

Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic ? cells.

Publications

Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic <b>β</b> cells.

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