文摘
Epidemiological, animal, and cell studies have demonstrated that nickel compounds are human carcinogens. The mechanisms of their carcinogenic actions remain to be investigated. p63, a close homologue of the p53 tumor suppressor protein, has been linked to cell fate determination and/or maintenance of self-renewing populations in several epithelial tissues, including skin, mammary gland, and prostate. x394;Np63, a dominant negative isoform of p63, is amplified in a variety of epithelial tumors including squamous cell carcinomas and carcinomas of the prostate and mammary glands. The present study shows that nickel suppressed x394;Np63 expression in a short-time treatment (up to 48 h). Nickel treatment caused activation of NF-κB. Blockage of NF-κB partially reversed nickel-induced x394;Np63 suppression. Nickel decreased interferon regulatory factor (IRF) 3 and IRF7, IKKε, and Sp100. Over-expression of IRF3 increased x394;Np63 expression suppressed by nickel. Nickel was able to activate p21, and its activation was offset by the over-expression of x394;Np63. In turn, elevated p63 expression counteracted the ability of nickel to restrict cell growth. The present study demonstrated that nickel decreased interferon regulatory proteins IRF3 and IRF7, and activated NF-κB, resulting in x394;Np63 suppression and then p21 up-regulation. x394;Np63 plays an important role in nickel-induced cell proliferation.