Constitutive expression of metallothionein-III (MT-III), but not MT-I, inhibits growth when cells become zinc deficient.
BHK cells were stably transformed with plasmid constructs that allowed constitutive expression of either mouse metallothionein-I (MT-I) or MT-III to determine whether these isoforms have different physiological properties. Cells expressing equivalent amounts of MT-I or MT-III could grow in 60-fold more cadmium than nontransfected cells and they were 2- to 3-fold more resistant to zinc, copper, and cobalt. The results suggest that the two MT isoforms detoxify these metals similarly. MT-III reduced the amount of zinc available to activate a zinc-sensitive reporter gene; MT-I actually increased the expression of the reporter gene at low concentrations of zinc. Cells expressing MT-I or MT-III also responded differently to zinc deficiency. When cells expressing MT-I were deprived of zinc, the amount of MT-I protein declined to undetectable levels, even though MT-I mRNA was still abundant, and cell proliferation was unaffected. In contrast, when cells expressing the MT-III gene were deprived of zinc, cell proliferation was arrested and MT-III protein persisted. These results suggest that MT-I does not compete with essential zinc-requiring proteins and is degraded, whereas MT-III competes for zinc and exacerbates zinc deficiency.
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D004351:Drug Resistance / Q000235:genetics; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000090023:Metallothionein 3; D008670:Metals / Q000633:toxicity; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D015032:Zinc / Q000172:deficiency* / Q000633:toxicity
D006131:Growth Inhibitors; D000090023:Metallothionein 3; D008670:Metals; D009419:Nerve Tissue Proteins; D008668:Metallothionein; D015032:Zinc