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1 Section of Physiology, Cornell University, Ithaca, New York 14853; 2 Fort Dodge Laboratories, Fort Dodge, Iowa 50501-0518; 3 Human Gene Therapy Research Institute, Des Moines, Iowa 50309; and 4 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Constant renewal of the intestinal epithelium is a highly coordinated process that has been subject to intense investigation, but its regulatory mechanisms are still essentially unknown. In this study, we have demonstrated that forced expression of the cyclin-dependent kinase inhibitors (CKIs) p27Kip1 and p21Cip1/WAF1 in human intestinal epithelial cells led to expression of differentiation markers at both the mRNA and protein levels. Cell differentiation was temporally dissociated from inhibition of retinoblastoma protein phosphorylation and growth arrest, already established 1 day after infection with recombinant adenoviruses. p27Kip1 proved significantly more efficient than p21Cip1/WAF1 in induction of cell differentiation. In contrast, forced expression of p16INK4a resulted in growth arrest without induction of differentiation markers. These results implicate both p27Kip1 and p21Cip1/WAF1 in the differentiation-timing process, but p21Cip1/WAF1 may act indirectly by increasing p27Kip1 levels. These results also suggest that induction of intestinal epithelial cell differentiation by CKIs is not related to their effects on the cell cycle and may involve interactions with cellular components other than cyclins and cyclin-dependent kinases.
cyclin-dependent kinase inhibitors; p21Cip1/WAF1; small intestine
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