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Cap43, a Novel Gene Specifically Induced by Ni²⁺ Compounds¹

The Nelson Institute of Environmental Medicine and The Kaplan Cancer Center, New York University Medical Center, 550 First Avenue, New York, NY 10016

To better understand the molecular mechanism(s) involved in the essentiality, toxicity, and/or carcinogenicity of nickel compounds, a mRNA differential display technique was used to identify gene(s) that were specifically induced by these carcinogens. Differential expression of several genes was observed in human lung A549 cells exposed to nickel subsulfide. One gene, Cap43, which expressed a 3.0-kb mRNA encoding a M_r 43,000 protein, was found to be induced within 4–6 h by either Ni₃S₂ or NiCl₂ in A549 cells and attained a level as high as 30-fold within 24–36 h of treatment. Twelve other tested metal compounds failed to induce Cap43 expression, leading to the conclusion that, with regard to metals, the induction of this gene was nickel-specific. Oxidative stress that is often caused by metals and heat shock did not induce Cap43 further, suggesting a specific nature in the signaling pathway involved in Cap43 induction. Activation of signaling pathways with vanadate did not induce Cap43 nor did trifluoperazine block its induction by nickel; however, okadaic acid, a serine/threonine phosphatase inhibitor, induced Cap43 to a greater extent than any nickel compound tested. Homocysteine did not induce Cap43 in a number of cell lines, with the exception of human endothelial cells. The Cap43 gene was found to be induced by nickel not only in all tested human and rodent cell lines in vitro but also in several rat organs after oral exposure to NiCl₂. We have found that the primary signal for Cap43 induction was an elevation of free intracellular Ca²⁺ caused by Ni²⁺ exposure because Cap43 was induced by calcium ionophores and its induction was attenuated by bis-(O-aminophenyl)-ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)-ester, a chelator of intracellular Ca²⁺. We found that the Cap43 gene was evolutionarily conserved and similarly regulated in humans, mice, and rats. Recent studies have shown that Cap43 is expressed at lower levels in colon cancer. Further studies of Cap43 regulation by Ca²⁺ should enhance our understanding of the role of Cap43 in cell function and cancer pathogenesis.

¹ This work was supported by Grants ES00260 and ES05512 from the National Institute of Environmental Health Sciences and Grant CA16037 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at The Nelson Institute of Environmental Medicine and The Kaplan Cancer Center, New York University Medical Center, 550 First Avenue, New York, NY 10016. Phone: (914) 351-2368 or (212) 263-5280; Fax: (914) 351-2118; E-mail: costam@charlotte.med.nyu.edu.

Received 12/15/97. Accepted 3/18/98.

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