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

doi:10.3389/fphys.2014.00226

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.

Highlights

SSTs exert their actions through a group of five G protein-coupled transmembrane receptors, termed somatostatin receptor 1-5 (SSTR1-5) (Yamada et al, 1992; Yasuda et al, 1992; Raynor et al, 1993; Reisine and Bell, 1995; Moldovan et al, 1998)
We summarize recent findings that pancreatic and duodenal homeobox-1 (PDX-1) acts as another transcription factor that is subject to the inhibitory regulation by SSTR5-mediated somatostatin signaling
A SSTR5 knockdown-induced increase of PDX-1 expression in mouse insulinoma MIN6 cells is accompanied by elevated expression of cyclin E and cdk4 and decreased expression of p21, p27, and p53, supporting previous studies showing that SSTR5 inhibits cell proliferation (Fagan et al, 1998; Feanny et al, 2008) and promotes apoptosis (Qiu et al, 2006)

Summary

Introduction

Somatostatin (SST) is a peptide hormone involved in a wide variety of biological functions including inhibition of endocrine and exocrine secretion; modulation of neurotransmission; motor and cognitive functions; inhibition of intestinal motility; absorption of nutrients and ions; vascular contractility; and regulation of cell proliferation, differentiation, inflammatory and immune responses (Patel, 1999; Wang et al, 2005a; Ballian et al, 2006, 2007; Florio, 2008). Recent studies show that RPL-1980 abolishes GLP-1-stimulated PDX-1 expression in mouse insulinoma β-TC6 cells (Zhou et al, 2012), indicating that SSTR5-mediated somatostatin signaling is a potential novel negative regulator for PDX-1 expression.

Results

Conclusion