Induction of metallothionein gene expression by epidermal growth factor and its inhibition by transforming growth factor-β and dexamethasone in rat hepatocytes

✍ Scribed by Pierre Moffatt; Gabriel L. Plaa; Francine Denizeau

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 874 KB
• Volume: 21
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.1840210423

✦ Synopsis

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 ZnSOl or dexamethasone (Dex) was also effective at inducing MT protein ( ~3 . 6 to 3.3 times) and &A.

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 &A expression was lost, whereas it had only minor inhibitory effects on DNA synthesis. Transforming growth factor beta (TGF-p), 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 TGFp had no effect. These results show that growth factors believed to play a role in liver regeneration can also modulate MT gene expression in uitro. 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.