Vasoactive intestinal peptide upregulates MUC2 intestinal mucin via CREB/ATF1.
VIP exerts a spectrum of effects as a potent anti-inflammatory factor. In addition, VIP increases expression of MUC2, a major intestinal secretory mucin. We therefore investigated the effects of VIP on the promoter activity of the 5'-flanking region of the MUC2 gene. VIP activated MUC2 transcription in human colonic epithelial cells via cAMP signaling to ERK and p38. cAMP/Epac/Rap1/B-Raf signaling was not involved in MUC2 reporter activation. Furthermore, activation of MUC2 transcription was independent of many of the reported downstream effectors of G protein-coupled receptors, such as PKC, Ras, Raf, Src, calcium, and phosphoinositide 3-kinase. VIP induced cAMP response element-binding protein (CREB)/ATF1 phosphorylation, and this was prevented by treatment with inhibitors of either MEK or p38 and by PKA and MSK1 inhibitor H89. CREB/ATF1 and c-Jun were shown to bind to an oligonucleotide encompassing a distal, conserved CREB/AP1 site in the 5'-flanking region of the MUC2 gene, and this cis element was shown to mediate promoter reporter activation by VIP. This study has identified a new, functional cis element within the MUC2 promoter and also a new pathway regulating MUC2 expression, thus providing further insight into the molecular mechanism of VIP action in the colon. These findings are relevant to the normal biology of the colonic mucosa as well as to the development of VIP as a therapeutic agent for treatment of inflammatory bowel disease.
Hokari
Ryota
R
Gastrointestinal Research Laboratory, Veterans' Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121, USA.
Lee
Hwayoung
H
Crawley
Suzanne C
SC
Yang
Stacey C
SC
Gum
James R
JR
Miura
Soichiro
S
Kim
Young S
YS
D051697:Activating Transcription Factor 1 / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D055262:Mucin-2; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000187:drug effects*; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051697:Activating Transcription Factor 1; D017362:Cyclic AMP Response Element-Binding Protein; C524625:MUC2 protein, human; D055262:Mucin-2; D009077:Mucins; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases