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  • Title: Metallothionein mediates the level and activity of nuclear factor kappa B in murine fibroblasts.
    Author: Butcher HL, Kennette WA, Collins O, Zalups RK, Koropatnick J.
    Journal: J Pharmacol Exp Ther; 2004 Aug; 310(2):589-98. PubMed ID: 15039454.
    Abstract:
    The zinc-binding protein metallothionein (MT) is associated with resistance to apoptosis. We examined whether MT regulates the zinc-dependent antiapoptotic transcription factor nuclear factor KappaB (NF-KappaB), which is up-regulated under many conditions that lead to elevated MT expression. NF-KappaB protein levels and NF-KappaB-dependent reporter gene activity were examined in clonal MT(+) (MT-WT) and MT(-) (MT-KO) fibroblastic cell lines. The amount of cellular NF-KappaB p65 protein in MT-KO was less than 20% of the amount in MT-WT cells, in accord with increased sensitivity of MT-KO cells to apoptosis. NF-KappaB p65 mRNA levels, and NF-KappaB p50 subunit and IKappaBalpha protein levels, were unchanged. NF-KappaB activity assessed by expression of a transfected NF-KappaB reporter construct was less than half that observed in MT-KO cells. Decreased nuclear localization of NF-KappaB p65 in MT-KO clones was not responsible for differences in activity. In fact, MT-KO cells had higher nuclear levels of NF-KappaB p65 than did MT-WT cells, despite a lower cellular NF-KappaB level and function, suggesting that metallothionein mediated the specific activity of NF-KappaB. Reconstitution of MT by stable incorporation of an MT-1 expression vector in MT-KO cells resulted in increased NF-KappaB p65 (but not IKappaBalpha or NF-KappaB p50), increased NF-KappaB-dependent reporter activity, and increased resistance to apoptosis. These data support the hypothesis that metallothionein positively regulates the cellular level and activity of NF-KappaB.
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