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Activation of Nuclear Factor B: Potential Role in Metallothionein-mediated Mitogenic Response¹

Department of Pharmacology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112

The antiapoptotic response and enhanced cellular proliferation observed in neoplastic cells on overexpression of metallothionein (MT) have been well documented. We have investigated the mechanisms associated with this phenomenon by using MT inducers that increased MT transcripts and stimulated growth in MCF-7 cells. A MT antisense phosphorothioate oligonucleotide inhibited growth induction by >50%, suggesting a potential role of MT in mediating the mitogenic effects of these agents. Mobility shift assays using oligonucleotides encompassing the consensus nuclear factor B (NFB) binding site and anti-MT antibody revealed activation and a specific interaction of NFB with MT. Cotransfection experiments using expression and reporter constructs demonstrated that MT caused transactivation of NFB. Gel shift assays using purified proteins showed a specific interaction between MT and the p50 subunit of NFB. These data indicate that MT may be involved in the interaction of NFB with the DNA-binding domain and further suggest a potential role for NFB in mediating the antiapoptotic effects of MT.

¹ Supported by a seed grant from the Tulane Cancer Center.

² To whom requests for reprints should be addressed, at Department of Pharmacology, SL 83, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112-2699. E-mail: agrawal@mailhost.tcs.tulane.edu.

Received 2/17/98. Accepted 4/10/98.

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