Activation of p73 and induction of Noxa by DNA damage requires NF-kappa B
Activation of p73 and induction of Noxa by DNA damage requires NF-kappa B
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DOI：
10.18632/aging.100026
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发表时间：
2009-03-01
期刊：
影响因子：
5.2
通讯作者：
Fearnhead, Howard O.
中科院分区：
文献类型：
--
作者：
Martin, Angel G.;Trama, Jason;Fearnhead, Howard O.
尽管转录因子NF-κ B通过上调已知的抗凋亡基因与抑制外源性凋亡信号如TNF α最明显相关，但NF-κ B也被认为是转化细胞中p53诱导的凋亡所必需的。然而，NF-κ B B在这一过程中的参与知之甚少。在这里，我们调查这一机制，并表明，在转化的MEFs缺乏NF-κ B（p65无效细胞）基因毒素诱导的细胞色素c的释放受到损害。为了进一步阐明NF-κ B B如何促进细胞凋亡，通过微阵列分析MEFs进行基因分析，揭示NF-κ B B是Noxa表达所必需的，Noxa是一种仅促细胞凋亡的BH 3蛋白，由基因毒素诱导并触发细胞色素c释放。此外，我们发现，在NF-κ B B的情况下，基因毒素处理不能诱导Noxa mRNA的表达。在基因毒素处理后，Noxa的表达已被证明直接受p53家族基因（如p73和p63）的调控。在这里，我们表明，只有在NF-κ B B的存在下，基因毒素处理后激活p73和p73诱导Noxa基因的表达，通过启动子中的p53元件。我们的数据为NF-κ B的缺失如何消除遗传毒素诱导的细胞凋亡提供了一个解释。
Although the transcription factor NF-kappa B is most clearly linked to the inhibition of extrinsic apoptotic signals suchas TNF alpha by upregulating known anti-apoptotic genes, NF-kappa B has also been proposed to be required for p53-induced apoptosis in transformed cells. However, the involvement of NF-kappa B in this process is poorly understood. Here we investigate this mechanism and show that in transformed MEFs lacking NF-kappa B (p65 null cells) genotoxin-induced cytochrome c release is compromised. To further address how NF-kappa B contributes to apoptosis, gene profiling by microarray analysis of MEFs was performed, revealing that NF-kappa B is required for expression of Noxa, a pro-apoptotic BH3-only proteinthat is induced by genotoxins and that triggers cytochrome c release. Moreover, we find that in the absence of NF-kappa B, genotoxin treatment cannot induce Noxa mRNA expression. Noxa expression had been shown to be regulated directly by genes of the p53 family, like p73 and p63, following genotoxin treatment. Here we show that p73 is activated after genotoxin treatment only in the presence of NF-kappa B and that p73 induces Noxa gene expression through the p53 element in the promoter. Together our data provides an explanation for how loss of NF-kappa B abrogates genotoxin-induced apoptosis.