期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 293, 期 5, 页码 G995-G1003出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00537.2006
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资金
- NCI NIH HHS [R01 CA044684, CA44684-12] Funding Source: Medline
- NICHD NIH HHS [R01 HD008299-33, R01 HD008299-34] Funding Source: Medline
- NIDDK NIH HHS [R01 DK040247, DK40247] Funding Source: Medline
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 the intestinal crypts in vivo.
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