Gastrin activates paracrine networks leading to induction of PAI-2 via MAZ and ASC-1.

Abstract

The gastric hormone gastrin regulates the expression of a variety of genes involved in control of acid secretion and also in the growth and organization of the gastric mucosa. One putative target is plasminogen activator inhibitor-2 (PAI-2), which is a component of the urokinase activator system that acts extracellularly to inhibit urokinase plasminogen activator (uPA) and intracellularly to suppress apoptosis. Previous studies have demonstrated that gastrin induces PAI-2 both in gastric epithelial cells expressing the gastrin (CCK-2) receptor and, via activation of paracrine networks, in adjacent cells that do not express the receptor. We have now sought to identify the response element(s) in the PAI-2 promoter targeted by paracrine mediators initiated by gastrin. Mutational analysis identified two putative response elements in the PAI-2 promoter that were downstream of gastrin-activated paracrine signals. One was identified as a putative MAZ site, mutation of which dramatically reduced both basal and gastrin-stimulated responses of the PAI-2 promoter by a mechanism involving PGE(2) and the small GTPase RhoA. Yeast one-hybrid screening identified the other as binding the activating signal cointegrator-1 (ASC-1) complex, which was shown to be the target of IL-8 released by gastrin. RNA interference (RNAi) knockdown of two subunits of the ASC-1 complex (p50 and p65) inhibited induction of PAI-2 expression by gastrin. The data reveal previously unsuspected transcriptional mechanisms activated as a consequence of gastrin-triggered paracrine networks and emphasize the elaborate and complex cellular control mechanisms required for a key component of tissue responses to damage and infection.

• Authors: Simon Almeida-Vega, Krista Catlow, Susan Kenny, Rod Dimaline, Andrea Varro
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 296 Issue 2 Pg. G414-23 (Feb 2009) ISSN: 0193-1857 [Print] United States
• PMID: 19074642 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCL8 protein, human
• DNA-Binding Proteins
• Gastrins
• Interleukin-8
• Plasminogen Activator Inhibitor 2
• RNA, Small Interfering
• TRIP4 protein, human
• Transcription Factors
• c-MYC-associated zinc finger protein
• RHOA protein, human
• gastrin 17
• rhoA GTP-Binding Protein
• Dinoprostone

Topics

• Base Sequence
• Binding Sites
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• DNA-Binding Proteins (genetics, metabolism)
• Dinoprostone (metabolism)
• Gastric Mucosa (metabolism)
• Gastrins (metabolism)
• Humans
• Interleukin-8 (metabolism)
• Molecular Sequence Data
• Mutation
• Paracrine Communication
• Plasminogen Activator Inhibitor 2 (genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Response Elements
• Signal Transduction
• Transcription Factors (genetics, metabolism)
• Transcriptional Activation
• Transfection
• Two-Hybrid System Techniques
• Up-Regulation
• rhoA GTP-Binding Protein (metabolism)