title: The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation.
abstract: The trefoil gene family of mucus cell-secreted proteins is a critical mediator of gastrointestinal mucosal restitution. Transcription of trefoil genes is induced during mucosal repair, but the regulatory mechanisms involved are unknown. Mice deficient in the intestine-specific peptide intestinal trefoil factor (ITF), in which colonic restitution is lethally impaired, showed reduced expression of the gastric trefoil genes SP and pS2, suggesting that trefoil peptides may individually regulate transcription of the entire family. In gastric cell lines, the trefoils were shown to act in a manner suggestive of immediate-early genes capable of auto- and cross-induction through cis-acting regulatory regions. Trefoil-mediated transcriptional regulation required activation of the Ras/MEK/MAP kinase signal transduction pathway. EGF receptor (EGF-R) activation was also necessary for trefoil auto- and cross-induction, and both spasmolytic polypeptide (SP) and ITF stimulation of gastric cell lines led to phosphorylation of EGF-R. Nevertheless, ITF and ITF-thioredoxin cell surface binding at 4 degrees C colocalized not with EGF-R, but with CD71, which is found in clathrin-coated pits, suggesting that integration of trefoil peptide responses may occur after internalization. As EGF-R expression is itself strongly induced after mucosal damage, the trefoil/EGF-R relationship may be pivotal in the generation and maintenance of the mucosal repair phenotype.
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: D
authors.initials: D
authors.lastname: Taupin
authors.forename: D C
authors.initials: DC
authors.lastname: Wu
authors.forename: W K
authors.initials: WK
authors.lastname: Jeon
authors.forename: K
authors.initials: K
authors.lastname: Devaney
authors.forename: T C
authors.initials: TC
authors.lastname: Wang
authors.forename: D K
authors.initials: DK
authors.lastname: Podolsky
mesh_terms: D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002966:Clathrin / Q000378:metabolism; D017931:DNA Primers; D066246:ErbB Receptors / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D017781:Genes, Immediate-Early; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D051379:Mice; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000502:physiology
chemical_list: D002966:Clathrin; D017931:DNA Primers; D006133:Growth Substances; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; C099037:TFF3 protein, rat; C000604008:Tff2 protein, rat; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018631:ras Proteins