P53-INDEPENDENT INDUCTION OF P21(WAF1 CIP1) EXPRESSION IN PERICENTRALHEPATOCYTES FOLLOWING CARBON-TETRACHLORIDE INTOXICATION/

The cyclin-dependent kinase, proliferating cell nuclear antigen, and s tress-activated protein kinase/c-jun NH2 terminal kinase inhibitor p21 (WAF1/CIP1) can induce G(1) arrest, and its expression coincides with the cessation of replication in many systems. We examined expression o f p21 during the early stages of carbon tetrachloride intoxication in the mouse liver and observed a dramatic increase in p21 RNA levels bet ween 4 and 8 h after administration. p21 expression, visualized by in situ hybridization, is induced in pericentral hepatocytes before carbo n tetrachloride-induced necrosis. Examination of c-fos and c-myc expre ssion patterns confirm that these immediate-early genes are induced in similar regions of the mouse liver. p21 induction is not dependent on p53; we observed similar levels and localization of p21 in wild-type and p53 null animals. Immunohistochemical localization of p21 and CCAA T/enhancer-binding protein expression shows that p21 protein accumulat ion is limited to a subset of CCAAT/enhancer-binding protein-positive hepatocytes. A second peak of periportal and intermediate zone-specifi c p21 gene expression, appearing 1-2 days after injection, is also p53 independent and may represent cell cycle checkpoints or postmitotic g rowth arrest. Sporadic p21 expression was also detected in pairs of he patocytes distributed throughout the liver acini in healthy animals. T ogether, these data suggest several roles for p21 in the liver in resp onse to toxicity, regeneration, and growth inhibition.