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Role of metal‐responsive transcription factor‐1 (MTF‐1) in EGF‐dependent DNA synthesis in primary hepatocytes
Author(s) -
Kimura Tomoki,
Itoh Norio,
Sone Tomomichi,
Kondoh Masuo,
Tanaka Keiichi,
Isobe Masakazu
Publication year - 2006
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20948
Subject(s) - epidermal growth factor , mapk/erk pathway , microbiology and biotechnology , biology , phosphorylation , hepatocyte , hepatocyte growth factor , kinase , transcription factor , extracellular , dna synthesis , chemistry , dna , cell culture , gene , biochemistry , receptor , in vitro , genetics
Metal‐responsive transcription factor‐1 (MTF‐1), which is involved in sensing heavy metal load, induces the transcription of several protective genes. The mouse Mtf‐1 gene is essential, and Mtf‐1 −/− embryos die from liver degeneration. We showed that DNA synthesis induced in hepatocytes by epidermal growth factor (EGF) was delayed by inhibition of MTF‐1. To inhibit MTF‐1 activity, MTFΔC, a C‐terminal deletion mutant of MTF‐1, was expressed by infection with the virus Ad5MTFΔC. Lactate dehydrogenase (LDH) release and/or caspase‐3/7 activation was not observed under our experimental conditions. The inhibitory effect of MTFΔC on EGF‐dependent DNA synthesis in hepatocytes was not eliminated by zinc addition. EGF‐dependent extracellular signal‐related kinase (ERK) phosphorylation, an essential reaction for EGF‐dependent DNA synthesis, was decreased in MTF‐1‐inhibited hepatocytes. Moreover, decrease of ERK phosphorylation was observed by using siRNA in MTF‐1‐downregulated hepatocytes. These results indicate that MTF‐1 is particularly important for proper hepatocyte proliferation. This is the first report to suggest the function of MTF‐1 in the ERK pathway. J. Cell. Biochem. 99: 485–494, 2006. © 2006 Wiley‐Liss, Inc.