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Induction of metallothionein gene expression by epidermal growth factor and its inhibition by transforming growth factor‐β and dexamethasone in rat hepatocytes
Author(s) -
Moffatt Pierre,
Plaa Gabriel L.,
Denizeau Francine
Publication year - 1995
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840210423
Subject(s) - epidermal growth factor , dna synthesis , biology , gene expression , messenger rna , metallothionein , endocrinology , stimulation , growth factor , medicine , transforming growth factor , protein biosynthesis , microbiology and biotechnology , gene , in vitro , receptor , biochemistry
Metallothionein (MT) is a small cysteine‐rich protein thought to be mainly involved in metal regulation and detoxification. The implication of MT in cell growth and differentiation has also been suggested. This latter hypothesis was further investigated in adult rat hepatocytes induced to proliferate by epidermal growth factor (EGF). Exposure of hepatocytes to EGF resulted in significant increases (≈twofold) in MT protein and MT‐1 messenger RNA (mRNA) levels, which were maximal after 48 hours. As revealed by nuclear run‐on analysis, these changes were the result of transcriptional activation. Increases of MT occurred concomitantly with stimulation of DNA synthesis (48 hours). Addition of ZnSO 4 or dexamethasone (Dex) was also effective at inducing MT protein (≈3.6 to 3.3 times) and mRNA. Combined addition of Zn and EGF produced an additive increase in MT protein and MT‐1 mRNA levels. When both Dex and EGF were present together, the EGF‐induced MT protein and mRNA expression was lost, whereas it had only minor inhibitory effects on DNA synthesis. Transforming growth factor beta (TGF‐β), a known antagonist of EGF on hepatocytes, blocked the EGF‐induced MT accumulation and stimulation of DNA synthesis. In addition, under the same conditions, the EGF‐induced c‐ fos mRNA accumulation was blocked by Dex whereas TGF‐β had no effect. These results show that growth factors believed to play a role in liver regeneration can also modulate MT gene expression in vitro. This modulation does not strictly parallel that of DNA synthesis. The possibility that c‐ fos stimulation may play a role in MT induction by EGF cannot be ruled out. (H EPATOLOGY 1995; 21:1038–1044.)