Cell Growth & Differentiation, Vol 8, Issue 9 951-961, Copyright © 1997 by American Association of Cancer Research

ARTICLES

p53-independent induction of p21WAF1/CIP1 expression in pericentral hepatocytes following carbon tetrachloride intoxication

MS Serfas, E Goufman, MH Feuerman, AL Gartel and AL Tyner
Department of Genetics, University of Illinois at Chicago 60607, USA.

The cyclin-dependent kinase, proliferating cell nuclear antigen, and stress-activated protein kinase/c-jun NH2 terminal kinase inhibitor p21WAF1/CIP1 can induce G1 arrest, and its expression coincides with the cessation of replication in many systems. We examined expression of p21 during the early stages of carbon tetrachloride intoxication in the mouse liver and observed a dramatic increase in p21 RNA levels between 4 and 8 h after administration. p21 expression, visualized by in situ hybridization, is induced in pericentral hepatocytes before carbon tetrachloride-induced necrosis. Examination of c-fos and c-myc expression 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 CCAAT/enhancer-binding protein expression shows that p21 protein accumulation is limited to a subset of CCAAT/enhancer-binding protein-positive hepatocytes. A second peak of periportal and intermediate zone-specific p21 gene expression, appearing 1-2 days after injection, is also p53 independent and may represent cell cycle checkpoints or postmitotic growth arrest. Sporadic p21 expression was also detected in pairs of hepatocytes distributed throughout the liver acini in healthy animals. Together, these data suggest several roles for p21 in the liver in response to toxicity, regeneration, and growth inhibition.

This article has been cited by other articles:

				A. Boitano, J. A. Ellman, G. D. Glick, and A. W. Opipari Jr. The Proapoptotic Benzodiazepine Bz-423 Affects the Growth and Survival of Malignant B Cells Cancer Res., October 15, 2003; 63(20): 6870 - 6876. [Abstract] [Full Text] [PDF]

				Y. H. Kwon, A. Jovanovic, M. S. Serfas, and A. L. Tyner The Cdk Inhibitor p21 Is Required for Necrosis, but It Inhibits Apoptosis following Toxin-induced Liver Injury J. Biol. Chem., August 8, 2003; 278(32): 30348 - 30355. [Abstract] [Full Text] [PDF]

				Y. H. Kwon, A. Jovanovic, M. S. Serfas, H. Kiyokawa, and A. L. Tyner p21 Functions to Maintain Quiescence of p27-deficient Hepatocytes J. Biol. Chem., October 25, 2002; 277(44): 41417 - 41422. [Abstract] [Full Text] [PDF]

				M. J. Bartosiewicz, D. Jenkins, S. Penn, J. Emery, and A. Buckpitt Unique Gene Expression Patterns in Liver and Kidney Associated with Exposure to Chemical Toxicants J. Pharmacol. Exp. Ther., June 1, 2001; 297(3): 895 - 905. [Abstract] [Full Text]

				J.-S. Park, L. Qiao, D. Gilfor, M. Y. Yang, P. B. Hylemon, C. Benz, G. Darlington, G. Firestone, P. B. Fisher, and P. Dent A Role for Both Ets and C/EBP Transcription Factors and mRNA Stabilization in the MAPK-dependent Increase in p21 Cip-1/WAF1/mda6 Protein Levels in Primary Hepatocytes Mol. Biol. Cell, September 1, 2000; 11(9): 2915 - 2932. [Abstract] [Full Text]

				J.-S. Park, S. Boyer, K. Mitchell, D. Gilfor, M. Birrer, G. Darlington, W. El Deiry, G. L. Firestone, K. Munger, V. Band, et al. Expression of Human Papilloma Virus E7 Protein Causes Apoptosis and Inhibits DNA Synthesis in Primary Hepatocytes via Increased Expression of p21Cip-1/WAF1/MDA6 J. Biol. Chem., January 7, 2000; 275(1): 18 - 28. [Abstract] [Full Text] [PDF]

				N. A. Timchenko, M. Wilde, and G. J. Darlington C/EBPalpha Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice Mol. Cell. Biol., April 1, 1999; 19(4): 2936 - 2945. [Abstract] [Full Text] [PDF]

				M. C. Yeung and A. S. Lau Tumor Suppressor p53 as a Component of the Tumor Necrosis Factor-induced, Protein Kinase PKR-mediated Apoptotic Pathway in Human Promonocytic U937 Cells J. Biol. Chem., September 25, 1998; 273(39): 25198 - 25202. [Abstract] [Full Text] [PDF]

				Y.-H. Choi, K.-B. Kim, H.-H. Kim, G.-S. Hong, Y.-K. Kwon, C.-W. Chung, Y.-M. Park, Z.-J. Shen, B. J. Kim, S.-Y. Lee, et al. FLASH Coordinates NF-kappa B Activity via TRAF2 J. Biol. Chem., June 29, 2001; 276(27): 25073 - 25077. [Abstract] [Full Text] [PDF]