Role of metal-responsive transcription factor-1 (MTF-1) in EGF-dependent DNA synthesis in primary hepatocytes.
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, MTFDeltaC, a C-terminal deletion mutant of MTF-1, was expressed by infection with the virus Ad5MTFDeltaC. Lactate dehydrogenase (LDH) release and/or caspase-3/7 activation was not observed under our experimental conditions. The inhibitory effect of MTFDeltaC 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.
Kimura
Tomoki
T
Department of Toxicology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan. tomoki@pharm.setsunan.ac.jp
Itoh
Norio
N
Sone
Tomomichi
T
Kondoh
Masuo
M
Tanaka
Keiichi
K
Isobe
Masakazu
M
D000818:Animals; D001483:Base Sequence; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D017384:Sequence Deletion; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000097809:Transcription Factor MTF-1
D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D004247:DNA; D004268:DNA-Binding Proteins; D004815:Epidermal Growth Factor; D007770:L-Lactate Dehydrogenase; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse