Nickel-induced down-regulation of ΔNp63 and its role in the proliferation of keratinocytes.
Nickel-induced down-regulation of ΔNp63 and its role in the proliferation of keratinocytes.
复制标题
镍诱导的αNp63 下调及其在角质形成细胞增殖中的作用。
DOI：
10.1016/j.taap.2011.03.024
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发表时间：
2011
影响因子：
3.8
通讯作者：
Shi,Xianglin
中科院分区：
文献类型：
--
作者：
Zhang,Zhuo;Li,Wenqi;Cheng,Senping;Yao,Hua;Zhang,Fan;Chang,Qingshan;Ke,Zunji;Wang,Xin;Son,Young-Ok;Luo,Jia;Shi,Xianglin
流行病学、动物和细胞研究表明，镍化合物是人类致癌物。其致癌作用的机制仍有待研究。p63是p53肿瘤抑制蛋白的密切同源物，已经与包括皮肤、乳腺和前列腺在内的几种上皮组织中的细胞命运决定和/或自我更新群体的维持相关联。Δ Np 63是p63的一种显性负性亚型，在多种上皮肿瘤中扩增，包括鳞状细胞癌和前列腺癌及乳腺癌。目前的研究表明，镍抑制Δ Np 63的表达在短时间内处理（长达48小时）。镍处理引起NF-κB活化。阻断NF-κB部分逆转镍诱导的Δ Np 63抑制。镍降低干扰素调节因子（IRF）3和IRF 7、IKKε和Sp100。过表达IRF 3增加镍抑制的Δ Np 63表达。镍能够激活p21，其激活被Δ Np 63的过表达所抵消。反过来，升高的p63表达抵消了镍限制细胞生长的能力。本研究表明，镍抑制了干扰素调节蛋白IRF 3和IRF 7的表达，激活了NF-κB，导致Δ Np 63的抑制和p21的上调。Δ Np 63在镍诱导的细胞增殖中起重要作用。
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 ΔNp63 expression suppressed by nickel. Nickel was able to activate p21, and its activation was offset by the over-expression of ΔNp63. 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 ΔNp63 suppression and then p21 up-regulation. ΔNp63 plays an important role in nickel-induced cell proliferation.