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Involvement of Interferon Regulatory Factor 1 and S100C/A11 in Growth Inhibition by Transforming Growth Factor ß1 in Human Hepatocellular Carcinoma Cells

Departments of ¹ Cell Biology and ² Bacteriology, Okayama University Graduate School of Medicine and Dentistry, Okayama, and ³ Department of General Medicine, Kyorin University School of Medicine, Tokyo, Japan

Growth inhibition by transforming growth factor (TGF)-ß1 has been attributed to the induction of cyclin-dependent kinase inhibitors, among which p21/Waf1 plays a major role in many biological contexts. In the present study, two new intracellular mediators for the induction of p21/Waf1 by TGF-ß1 were identified in a human hepatocellular carcinoma cell line (JHH-5) expressing mutant-type p53. After addition of TGF-ß1 to JHH-5 cells, a marked increase of the p21/Waf1 expression preceded the inhibition of DNA synthesis. Expression of IFN regulatory factor (IRF)-1, a known transacting factor for p21/Waf1 promoter, was elevated just before or in parallel with the increase of p21/Waf1. Transduction of antisense IRF-1 inhibited the increase in p21/Waf1 in JHH-5 cells treated with TGF-ß1 and partially released the cells from the growth arrest by TGF-ß1. Expression of S100C/A11, a member of the Ca²⁺-binding S100 protein family, also markedly increased after addition of TGF-ß1. S100C/A11 protein was translocated to and accumulated in nuclei of TGF-ß1-treated JHH-5 cells, where p21/Waf1 was concomitantly accumulated. When a recombinant S100C/A11 protein was introduced into nuclei of JHH-5 cells, DNA synthesis was markedly inhibited in a dose-dependent manner in the absence of TGF-ß1. Prior transfection of p21/Waf1-targeted small interfering RNA efficiently blocked decrease of DNA synthesis in JHH-5 cells caused by TAT-S100C/A11 or TGF-ß1 and markedly inhibited expression of p21/Waf1 protein in the cells. These results indicate that IRF-1 and S100C/A11 mediate growth inhibition by TGF-ß1 via induction of p21/Waf1.

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