Active repression of antiapoptotic gene expression by ReIA(p65) NF-κB
Active repression of antiapoptotic gene expression by ReIA(p65) NF-κB
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DOI：
10.1016/s1097-2765(04)00131-5
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发表时间：
2004-03-26
期刊：
影响因子：
16
通讯作者：
Perkins, ND
中科院分区：
文献类型：
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作者：
Campbell, KJ;Rocha, S;Perkins, ND
随着NF-kappaB在癌症中的新作用，了解其对肿瘤进展和治疗相关刺激的反应是很重要的。在这里，我们证明了NF-kappaB由细胞毒性刺激，如紫外光（UV-C）和化疗药物柔红霉素/阿霉素诱导，在功能上与炎性细胞因子TNF不同，是抗凋亡基因表达的活性抑制因子。令人惊讶的是，这些作用是由ReIA(p65) NF-kappaB亚基介导的。此外，UV-C和柔红霉素抑制tnf诱导的NF-kappaB转激活，表明这是一个显性效应。与此一致的是，机制研究表明，UV-C和柔红霉素诱导ReIA与组蛋白去乙酰化酶的关联。因此，ReIA可以是其靶基因的激活因子和抑制因子，这取决于它被诱导的方式。这对于NF-kappabeta在肿瘤发生中的作用以及NF-kappabeta抑制剂在癌症治疗中的应用具有重要意义。
With the emerging role of NF-kappaB in cancer it is important that its responses to stimuli relevant to tumor progression and therapy are understood. Here, we demonstrate that NF-kappaB induced by cytotoxic stimuli, such as ultraviolet light (UV-C) and the chemotherapeutic drugs daunorubicin/doxorubicin, is functionally distinct to that seen with the inflammatory cytokine TNF and is an active repressor of antiapoptotic gene expression. Surprisingly, these effects are mediated by the ReIA(p65) NF-kappaB subunit. Furthermore, UV-C and daunorubicin inhibit TNF-induced NF-kappaB transactivation, indicating that this is a dominant effect. Consistent with this, mechanistic studies reveal that UV-C and daunorubicin induce the association of ReIA with histone deacetylases. ReIA can therefore be both an activator and repressor of its target genes, dependent upon the manner in which it is induced. This has important implications for the role of NF-kappabeta in tumorigenesis and the use of NF-kappabeta inhibitors in cancer therapy.