REGULATION OF CYCLIN-DEPENDENT KINASE INHIBITOR P21(WAF1 CIP1/SDI1) GENE-EXPRESSION IN HEPATIC REGENERATION/

WAF1/Cip1/Sdi1 (p21) is the prototype of a family of proteins that inh ibit cyclin-dependent kinases and regulate cell cycle progression in e ukaryotic cells. In addition to normal cell cycle progression, p21 is involved in growth suppression mediated by p53 and transforming growth factor beta (TGF beta), differentiation, and apoptosis. To gain insig ht into the possible involvement of p21 in liver cell growth, the expr ession and regulation of the p21 gene was evaluated in rodent models o f liver regeneration and specimens of human liver diseases. Little p21 mRNA was detected in normal liver tissue. After growth stimulation in vivo by 70% partial hepatectomy (PH), the p21 transcript was upregula ted in a biphasic manner, with enhanced expression during G1 phase and following S phase. The induction of p21 after PH was regulated primar ily at the post-transcriptional level and was due to enhanced mRNA sta bility. Inhibition of protein synthesis with cycloheximide rapidly ind uced p21 expression, primarily by post-transcriptional stabilization o f the transcript. Hepatic p21 mRNA was also induced by dietary protein deprivation in normal mice. Expression of the p21 gene after PH was s imilar in p53-deficient (p53 -/-) and wild-type mice, but was p53 depe ndent following protein deprivation. Primary hepatocytes in culture de monstrated increased p21 expression after treatment with hepatocyte gr owth factor, TGF beta, and activin A. p21 mRNA was upregulated in huma n liver diseases, suggesting a possible role in hepatic growth regulat ion in pathologic states. The present study demonstrates that p21 is r egulated by p53-dependent and -independent pathways in the liver, and is influenced by both mitogenic and growth inhibitory stimuli.