J. Biochem, 1997, Vol. 121, No. 4 677-683
© 1997 Japanese Biochemical Society
research-article |
Analysis of IFN-
-Induced Cell Cycle Arrest and Cell Death in Hepatocytes1
,*
*Department of Biomolecular Engineering, Tokyo Institute of Technology 4259 Nagatsuda, Midori-ku, Yokohama 226
Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine Honjo 2-2-1, Kumamoto 860
2To whom correspondence should be addressed. Tel: +81-045-924-5801, Fax: +81-045-924-5815 E-mail: ywatanab{at}bio.titech.ac.jp
The mechanism by which IFN-
induces cell cycle arrest and cell death in primary cultured hepatocytes was examined. The cell death exhibits apoptotic characters such as the appearance of apoptotic bodies and DNA fragmentation. IFN- induced cell cycle arrest at the initial stage, followed by cell death. A protein synthesis inhibitor, cycloheximide, significantly inhibited cell death, implying that IFN- induces de novo proteins involved in the death of hepatocytes. One of the most important apoptosis-related proteins, p53, was induced by IFN- in hepatocytes in a dose- and time-dependent manner. Northern blot analysis demonstrated that IFN- enhanced p53 mRNA expression as well as p21WAF1/C1p1/Sdf1 mRNA expression, which is mediated by the increased expression of the p53 protein. Interestingly, IFN- also induced cell death in p53-deficient hepatocytes. The cell death occurred rather earlier in p53-deficient cells than in normal hepatocytes. However, the cell death was not accompanied by apoptotic bodies. Therefore, IFN--induced hepatocyte cell death is p53-independent, and p53 may contribute to the apoptotic characters. In conclusion, IFN- is supposed to cause cell cycle arrest by inducing p53 and p21WAF1/clp1/Sdl1 and it was demonstrated that IFN- induces p53-independent cell death in primary cultured hepatocytes.
1This work was partly supported by the New Energy and Industrial Technology Development Organization (NEDO), Grant No. 1110.
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