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CELLULAR AND MOLECULAR

Metallothionein Mediates the Level and Activity of Nuclear Factor KB in Murine Fibroblasts

Departments of Oncology (J.K.), Microbiology and Immunology (J.K.), Pathology (J.K.), and Physiology and Pharmacology (H.L.B., J.K.), University of Western Ontario, London, Ontario, Canada; London Regional Cancer Centre, London, Ontario, Canada (H.L.B., W.A.K., O.C., J.K.); and Mercer University School of Medicine, Division of Basic Medical Sciences, Macon, Georgia (R.K.Z.)

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 KB (NF-KB), which is up-regulated under many conditions that lead to elevated MT expression. NF-KB protein levels and NF-KB-dependent reporter gene activity were examined in clonal MT(+) (MT-WT) and MT(–) (MT-KO) fibroblastic cell lines. The amount of cellular NF-KB 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-KB p65 mRNA levels, and NF-KB p50 subunit and IKB protein levels, were unchanged. NF-KB activity assessed by expression of a transfected NF-KB reporter construct was less than half that observed in MT-KO cells. Decreased nuclear localization of NF-KB p65 in MT-KO clones was not responsible for differences in activity. In fact, MT-KO cells had higher nuclear levels of NF-KB p65 than did MT-WT cells, despite a lower cellular NF-KB level and function, suggesting that metallothionein mediated the specific activity of NF-KB. Reconstitution of MT by stable incorporation of an MT-1 expression vector in MT-KO cells resulted in increased NF-KB p65 (but not IKB or NF-KB p50), increased NF-KB-dependent reporter activity, and increased resistance to apoptosis. These data support the hypothesis that metallothionein positively regulates the cellular level and activity of NF-KB.

Address correspondence to: Dr. James Koropatnick, London Regional Cancer Centre, 790 Commissioners Road East, London, Ontario, Canada N6A 4L6. E-mail: jkoropat{at}uwo.ca

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