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Apoptosis induced by transforming growth factor-β in fetal hepatocyte primary cultures Sánchez, Aránzazu Álvarez Barrientos, Alberto Benito, Manuel Fabregat Romero, Isabel Apoptosi Efectes secundaris dels medicaments Fetge Metabolisme Apoptosis Drug side effects Liver Metabolism Transforming growth factor-beta (TGF-beta), a growth regulator of fetal hepatocytes in primary culture, also regulates death of these cells. Dose-response analysis showed that the TGF-beta concentration needed to induce hepatocyte death (2.5 ng/ml) was 5 times that needed to inhibit growth in these cells (0.5 ng/ml). In response to TGF-beta, hepatocytes induced DNA fragmentation and the appearance of nuclei with a DNA content lower than 2C (diploid content), typical of a programmed cell death model. TGF-beta-induced apoptosis in fetal hepatocytes was preceded by an induction of reactive oxygen species production and a decrease in the glutathione intracellular content, indicating that this factor induces oxidative stress in fetal hepatocytes. Studies performed to analyze levels of c-fos mRNA, a gene whose expression is modulated by redox state, demonstrated that only high, apoptotic concentrations of TGF-beta (2.5 ng/ml) produced an increase in the mRNA levels of this gene, the level of induction being similar to that found when cells were incubated in the presence of tert-butyl hydroperoxide. Gel mobility shift assays showed that the c-fos-induced expression was coincident with an increase in AP-1 activity. Finally, cell death induced by TGF-beta in fetal hepatocytes was partially blocked by radical scavengers, which decreased the percentage of apoptotic cells, whereas these agents did not modify the growth-inhibitory effect elicited by TGF-beta in these cells. In summary, the results presented in this paper provide evidence for the involvement of an oxidative process in the apoptosis elicited by TGF-beta in fetal hepatocytes. 2021-11-17T14:04:58Z 2021-11-17T14:04:58Z 1996-03-29 2021-11-17T14:04:58Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 0021-9258 https://hdl.handle.net/2445/181306 579693 8631767 eng Reproducció del document publicat a: https://doi.org/10.1074/jbc.271.13.7416 Journal of Biological Chemistry, 1996, vol. 271, num. 13, p. 7416-7422 https://doi.org/10.1074/jbc.271.13.7416 (c) American Society for Biochemistry and Molecular Biology, 1996 info:eu-repo/semantics/openAccess 7 p. application/pdf American Society for Biochemistry and Molecular Biology Articles publicats en revistes (Ciències Fisiològiques)