Down-regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5: a novel mechanism for inhibition of cellular proliferation and insulin secretion by somatostatin

Guisheng Zhou; Jim Sinnett-Smith; Shi-He Liu; Juehua Yu; James Wu; Robbi Sanchez; Stephen J Pandol; Ravinder Abrol; John Nemunaitis; Enrique Rozengurt; F Charles Brunicardi

doi:10.3389/fphys.2014.00226

Down-regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5: a novel mechanism for inhibition of cellular proliferation and insulin secretion by somatostatin

Front Physiol. 2014 Jun 25:5:226. doi: 10.3389/fphys.2014.00226. eCollection 2014.

Authors

Affiliations

¹ Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA ; CURE: Digestive Disease Research Center, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
² CURE: Digestive Disease Research Center, David Geffen School of Medicine at University of California Los Angeles, CA, USA ; Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
³ Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
⁴ CURE: Digestive Disease Research Center, David Geffen School of Medicine at University of California Los Angeles, CA, USA ; Department of Medicine at Cedars Sinai Medical Center Los Angeles, CA, USA ; Veterans Affairs Los Angeles, CA, USA.
⁵ Materials and Process Simulation Center, California Institute of Technology Pasadena, CA, USA.
⁶ Gradalis, Inc., Dallas, TX, USA ; Mary Crowley Cancer Research Centers Dallas, TX, USA.

Abstract

Somatostatin (SST) is a regulatory peptide and acts as an endogenous inhibitory regulator of the secretory and proliferative responses of target cells. SST's actions are mediated by a family of seven transmembrane domain G protein-coupled receptors that comprise five distinct subtypes (SSTR1-5). SSTR5 is one of the major SSTRs in the islets of Langerhans. Homeodomain-containing transcription factor pancreatic and duodenal homeobox-1 (PDX-1) is essential for pancreatic development, β cell differentiation, maintenance of normal β cell functions in adults and tumorigenesis. Recent studies show that SSTR5 acts as a negative regulator for PDX-1 expression and that SSTR5 mediates somatostatin's inhibitory effect on cell proliferation and insulin expression/excretion through down-regulating PDX-1 expression. SSTR5 exerts its inhibitory effect on PDX-1 expression at both the transcriptional level by down-regulating PDX-1 mRNA and the post-translational level by enhancing PDX-1 ubiquitination. Identification of PDX-1 as a transcriptional target for SSTR5 may help in guiding the choice of therapeutic cancer treatments.

Keywords: G protein-coupled receptors; pancreatic and duodenal homeobox-1; single nucleotide polymorphisms; somatostatin; somatostatin receptor.

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Review

Abstract

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