Comparative effects of overexpression of p21(CKip1) and p21(Cip1/Waf1) growth and differentiation in human colon carcinoma cells

Recent studies have shown that decreased expression of p27(Kip1) is associa ted with high grade tumors and am unfavorable prognosis in several types of human cancer. To clarify the role of p27(Kip1) in colon cancer, we have ov erexpressed this protein in the HT29 colon cancer cell line. The derivative s displayed an increase in the p27(Kip1) protein in cyclin E/CDK2 immunopre cipitates and :a decrease in cyclin E-associated kinase activity when compa red to vector control clones, providing evidence that the overexpressed pro tein was functional. Clones with a high level of p27(Kip1) displayed partia l growth inhibition in monolayer culture and a decrease in plating efficien cy, even though they expressed increased levels of the cyclin D1 protein. U sing alkaline phosphatase expression as a marker, we found that the p27(Kip 1) overexpressor clones displayed a 2-3-fold increase in sensitivity to ind uction of differentiation by 2 mM sodium butyrate, In contrast to these res ults, derivatives of HT29 cells that stably overexpressed p21(Cip1/Waf1) di splayed decreased sensitivity to the induction of differentiation. These fi ndings may explain why decreased levels of p27(Kip1) in certain human cance rs is associated with high grade (poorly differentiated) tumors, and sugges t that strategies that increase the level of p27(Kip1) may be useful in can cer therapy.