Reduced expression of p27kip1 and increased hepatocyte proliferation in p53-deficient mice.

Livers from wild-type and p53-deficient mice were analyzed for the expression of cell-cycle regulatory proteins in an attempt to determine the mechanism for the increased proliferation of liver cells in p53-deficient mice associated with enhanced susceptibility to aflatoxin-induced liver cancer. The most striking difference found was a significant reduction of the cyclin-dependent kinase inhibitor p27(kip1) in the livers of 3-mo-old p53-/- mice, whereas only small changes were found in the expression of cyclins, cyclin-dependent kinases, and the inhibitors p21(cip1) and p16(ink4a). Relative to wild-type liver, the amounts of p27(kip1) mRNA were reduced at both 1 and 3 mo, whereas the levels of p27(kip1) protein were decreased only at 3 mo. These results identify an uncharacterized link between the expression of p53 and p27(kip1) that may involve both transcriptional and post-transcriptional regulation and allow hepatocytes to continue to proliferate after 3 wk of age. We postulate that this increased proliferation leads to increased susceptibility to aflatoxin-induced hepatocarcinogenesis.