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Am J Physiol Gastrointest Liver Physiol 279: G1282-G1291, 2000;
0193-1857/00 $5.00
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Vol. 279, Issue 6, G1282-G1291, December 2000

Transcription factor NF-kappa B participates in regulation of epithelial cell turnover in the colon

Mehmet Sait Inan1, Veronica Tolmacheva1, Qiang-Shu Wang2, Daniel W. Rosenberg2, and Charles Giardina1

1 Department of Molecular and Cell Biology and 2 Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269

The transcription factor nuclear factor (NF)-kappa B regulates the expression of genes that can influence cell proliferation and death. Here we analyze the contribution of NF-kappa B to the regulation of epithelial cell turnover in the colon. Immunohistochemical, immunoblot, and DNA binding analyses indicate that NF-kappa B complexes change as colonocytes mature: p65-p50 complexes predominate in proliferating epithelial cells of the colon, whereas the p50-p50 dimer is prevalent in mature epithelial cells. NF-kappa B1 (p50) knockout mice were used to study the role of NF-kappa B in regulating epithelial cell turnover. Knockout animals lacked detectable NF-kappa B DNA binding activity in isolated epithelial cells and had significantly longer crypts with a more extensive proliferative zone than their wild-type counterparts (as determined by proliferating cell nuclear antigen staining and in vivo bromodeoxyuridine labeling). Gene expression profiling reveals that the NF-kappa B1 knockout mice express the potentially growth-enhancing tumor necrosis factor (TNF)-alpha and nerve growth factor-alpha genes at elevated levels, with in situ hybridization localizing some of the TNF-alpha expression to epithelial cells. TNF-alpha is NF-kappa B regulated, and its upregulation in NF-kappa B1 knockouts may result from an alleviation of p50-p50 repression. NF-kappa B complexes may therefore influence cell proliferation in the colon through their ability to selectively activate and/or repress gene expression.

nuclear factor-kappa B; cell proliferation; tumor necrosis factor-alpha ; nerve growth factor-alpha


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