title: Cell-specific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth.
abstract: Insulin-like growth factor I (IGF-I) potently stimulates intestinal growth. Insulin receptor substrate-1 (IRS-1) mediates proliferative and antiapoptotic actions of IGF-I in cell lines, but its in vivo relevance in intestine is not defined. This study tested the hypothesis that there is cell type-specific dependence on IRS-1 as a mediator of IGF-I action. Length, mass, crypt cell proliferation, and apoptosis were measured in small intestine and colon of IRS-1-null mice and wild-type (WT) littermates and in colon of IRS-1-null or WT mice expressing IGF-I transgenes. Expression of IGF-I receptor and signaling intermediates was examined in intestine of WT and IRS-1-null mice, cultured intestinal epithelial cells, and myofibroblasts. Absolute IRS-1 deficiency reduced mucosal mass in jejunum and colon, but effects were more pronounced in colon. Muscularis mass was decreased in both segments. In IGF-I transgenics, IRS-1 deficiency significantly attenuated IGF-I-stimulated growth of colonic mucosa and abolished antiapoptotic but not mitogenic effects of IGF-I transgene on crypt cells. IGF-I-induced muscularis growth was unaffected by IRS-1 deficiency. In intestinal epithelial cells, IRS-1 was expressed at higher levels than IRS-2 and was preferentially activated by IGF-I. In contrast, IGF-I activated both IRS-1 and IRS-2 in intestinal myofibroblasts and IRS-2 activation was upregulated in IRS-1-null myofibroblasts. We conclude that the intestinal epithelium but not the muscularis requires IRS-1 for normal trophic actions of IGF-I and that IRS-1 is required for antiapoptotic but not mitogenic effects of IGF-I in the intestinal crypts in vivo.
authors.affiliation: Department of Cell and Molecular Physiology, UNC-Chapel Hill, NC 27599-7545, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Simmons
authors.forename: Y
authors.initials: Y
authors.lastname: Ling
authors.forename: H
authors.initials: H
authors.lastname: Wilkins
authors.forename: C R
authors.initials: CR
authors.lastname: Fuller
authors.forename: A J
authors.initials: AJ
authors.lastname: D'Ercole
authors.forename: James
authors.initials: J
authors.lastname: Fagin
authors.forename: P K
authors.initials: PK
authors.lastname: Lund
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D009929:Organ Size; D010750:Phosphoproteins / Q000172:deficiency* / Q000502:physiology*