Ms. Serfas et al., P53-INDEPENDENT INDUCTION OF P21(WAF1 CIP1) EXPRESSION IN PERICENTRALHEPATOCYTES FOLLOWING CARBON-TETRACHLORIDE INTOXICATION/, Cell growth & differentiation, 8(9), 1997, pp. 951-961
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.