Nickel-induced down-regulation of ΔNp63 and its role in the proliferation of keratinocytes

Zhuo Zhang, Wenqi Li, Senping Cheng, Hua Yao, Fan Zhang, Qingshan Chang, Zunji Ke, Xin Wang, Young Ok Son, Jia Luo, Xianglin Shi

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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 δNp63, 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 δNp63 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 ΔNp63 suppression. Nickel decreased interferon regulatory factor (IRF) 3 and IRF7, IKKε, and Sp100. Over-expression of IRF3 increased εNp63 expression suppressed by nickel. Nickel was able to activate p21, and its activation was offset by the over-expression of εNp63. 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 εNp63 suppression and then p21 up-regulation εNp63 plays an important role in nickel-induced cell proliferation.

Original languageEnglish
Pages (from-to)235-243
Number of pages9
JournalToxicology and Applied Pharmacology
Issue number3
StatePublished - Jun 15 2011

Bibliographical note

Funding Information:
This research is supported by NIH grant R01ES015518 .


  • Cell proliferation
  • Interferon regulatory factor (IRF)
  • Keratinocytes
  • NF-κB
  • Nickel chloride
  • P21
  • εNp63

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology


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