Insulin receptor substrate-1 deficiency promotes apoptosis in the putative intestinal crypt stem cell region, limits Apcmin/+ tumors, and regulates Sox9.
Reduced apoptosis of crypt stem/progenitor cells and elevated insulin and IGFs are linked to colon cancer risk. Insulin receptor substrate-1 (IRS-1) mediates the actions of insulin, IGF-I, and IGF-II, but the role of endogenous IRS-1 in crypt apoptosis and cancer is undefined. Using IRS-1(-/-), IRS-1(+/-), and IRS-1(+/+) mice, we tested the hypothesis that reduced IRS-1 expression increases apoptosis of intestinal crypt cells and protects against Apc(min/+) (Min)/beta-catenin-driven intestinal tumors. Expression of Sox9, a transcriptional target of Tcf/beta-catenin and putative biomarker of crypt stem cells, was assessed in intestine of different IRS-1 genotypes and cell lines. Irradiation-induced apoptosis was significantly increased in the crypts and crypt stem cell region of IRS-1-deficient mice. Tumor load was significantly reduced by 31.2 +/- 14.6% in IRS-1(+/-)/Min and by 64.1 +/- 7.6% in IRS-1(-/-)/Min mice, with more prominent reductions in tumor number than size. Compared with IRS-1(+/+)/Min, IRS-1(-/-)/Min mice had fewer Sox9-positive cells in intestinal crypts and reduced Sox9 mRNA in intestine. IRS-1 overexpression increased Sox9 expression in an intestinal epithelial cell line. We conclude that even small reductions in endogenous IRS-1 increase apoptosis of crypt stem or progenitor cells, protect against beta-catenin-driven intestinal tumors, and reduce Sox9, a Tcf/beta-catenin target and putative stem/progenitor cell biomarker.
Ramocki
Nicole M
NM
Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, North Carolina 27599-7545, USA. nicole_ramocki@med.unc.edu or empk@med.unc.edu
Wilkins
Heather R
HR
Magness
Scott T
ST
Simmons
James G
JG
Scull
Brooks P
BP
Lee
Ginny H
GH
McNaughton
Kirk K
KK
Lund
P Kay
PK
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D005786:Gene Expression Regulation; D017491:Genes, APC; D006579:Heterozygote; D006609:High Mobility Group Proteins / Q000235:genetics*; D055504:Insulin Receptor Substrate Proteins; D007413:Intestinal Mucosa / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects / Q000648:ultrastructure; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008871:Microvilli; D009154:Mutation; D055758:SOX9 Transcription Factor; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects; D014157:Transcription Factors / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D006609:High Mobility Group Proteins; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D014157:Transcription Factors