Role of metal-responsive transcription factor-1 (MTF-1) in EGF-dependent DNA synthesis in primary hepatocytes

✍ Scribed by Tomoki Kimura; Norio Itoh; Tomomichi Sone; Masuo Kondoh; Keiichi Tanaka; Masakazu Isobe

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 204 KB
• Volume: 99
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.20948

✦ Synopsis

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 À/À 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, MTFDC, a C-terminal deletion mutant of MTF-1, was expressed by infection with the virus Ad5MTFDC. Lactate dehydrogenase (LDH) release and/or caspase-3/7 activation was not observed under our experimental conditions. The inhibitory effect of MTFDC 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.