Cap43, a Novel Gene Specifically Induced by Ni2+ Compounds1

To better understand the molecular mechanism(s) involved in the essentiality, toxicity, and/or carcinogenicity of nickel compounds, a niKN A differential display technique was used to identify gene(s) that were specifically induced by these carcinogens. Differential expression of sev eral genes was observed in human lung A549 cells exposed to nickel subsulfide. One gene, Cap43, which expressed a 3.0-kb niKNA encoding a U, 43,000 protein, was found to be induced within 4-6 h by either Ni.S, or Ni( I. 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 Cm* caused by Ni' ' exposure because Cap43 was induced by calcium ionophores and its induction was attenuated by bis-(0-aminophenyl)-ethane-/V,A',/V',/V'-tetraacetic acid tetralacetoxymethyD-ester, a chelator of intracellular ( ';r '. 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 <'¡r' should enhance our understanding of the role of Cap43 in cell function and cancer pathogenesis.