The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation

The trefoil gene family of mucus cell-secreted proteins is a critical media tor of gastrointestinal mucosal restitution. Transcription of trefoil genes is induced during mucosal repair, but the regulatory mechanisms involved a re unknown. Mice deficient in the intestine-specific peptide intestinal tre foil factor (ITF), in which colonic restitution is lethally impaired, showe d reduced expression of the gastric trefoil genes SP and pS2, suggesting th at trefoil peptides may individually regulate transcription of the entire f amily. In gastric cell lines, the trefoils were shown to act in a manner su ggestive of immediate-early genes capable of auto- and cross-induction thro ugh cis-acting regulatory regions. Trefoil-mediated transcriptional regulat ion required activation of the Ras/MEK/MAP kinase signal transduction pathw ay. EGF receptor (EGF-R) activation was also necessary for trefoil auto- an d cross-induction, and both spasmolytic polypeptide (SP) and ITF stimulatio n of gastric cell lines led to phosphorylation of EGF-R. Nevertheless, ITF and ITF-thioredoxin cell surface binding at 4 degrees C colocalized not wit h EGF-R, but with CD71, which is found in clathrin-coated pits, suggesting that integration of trefoil peptide responses may occur after internalizati on. As EGF-R expression is itself strongly induced after mucosal damage, th e trefoil/EGF-R relationship may be pivotal in the generation and maintenan ce of the mucosal repair phenotype.