Stabilization of p53 is a novel mechanism for proapoptotic function of NF-κB
Stabilization of p53 is a novel mechanism for proapoptotic function of NF-κB
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DOI：
10.1074/jbc.m313435200
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发表时间：
2004-06-25
影响因子：
4.8
通讯作者：
Chiao, PJ
中科院分区：
文献类型：
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作者：
Fujioka, S;Schmidt, C;Chiao, PJ
NF-kappaB转录因子具有促凋亡和抗凋亡活性；然而，NF-kappaB诱导细胞凋亡的机制尚不清楚。为了阐明NF-kappaB如何调节促凋亡信号传导，我们使用野生型、ikk1（-/-）、ikk2（-/-）、rela（-/-）小鼠成纤维细胞、mdapanc28 /Puro、mdapanc28 /IkappaBalphaM和HCT116/p53（+/+）和HCT116/p53（-/-）细胞进行了功能分析，并使用抗癌药物强力霉素作为产生凋亡刺激的超氧化物诱导剂。在本报告中，我们发现强力霉素增加了超氧化物的产生，随后激活了NF-kappaB，进而上调了p53的表达，增加了p53的稳定性和DNA结合活性。因此，nf - kappab依赖性p53活性诱导了p53调控基因PUMA和p21（waf1）的表达以及细胞凋亡。重要的是，缺乏RelA、IKK和p53以及显性IkappaBalpha（ikappabpham）负表达抑制nf - kappab依赖性p53的激活和凋亡。强力霉素诱导的NF-kappaB激活在HCT116/p53（+/+）细胞中不受抑制。我们的研究结果表明，NF-kappaB在激活野生型p53肿瘤抑制因子中发挥重要作用，从而启动促凋亡信号传导，以响应超氧化物的过度产生。因此，这些发现揭示了nf - kappab调控促凋亡信号传导的机制。
Both pro- and antiapoptotic activities of NF-kappaB transcription factor have been observed; however, less is known about the mechanism by which NF-kappaB induces apoptosis. To elucidate how NF-kappaB regulates proapoptotic signaling, we performed functional analyses using wild-type, ikk1(-/-), ikk2(-/-), rela(-/-) murine fibroblasts, MDAPanc-28/Puro, MDAPanc-28/IkappaBalphaM, and HCT116/p53(+/+) and HCT116/p53(-/-) cells with investigational anticancer agent doxycycline as a superoxide inducer for generating apoptotic stimulus. In this report, we show that doxycycline increased superoxide generation and subsequently activated NF-kappaB, which in turn up-regulated p53 expression and increased the stability and DNA binding activity of p53. Consequently, NF-kappaB-dependent p53 activity induced the expression of p53-regulated genes PUMA and p21(waf1) as well as apoptosis. Importantly, lack of RelA, IKK, and p53 as well as expression of a dominant negative IkappaBalpha(IkappaBalphaM) inhibited NF-kappaB-dependent p53 activation and apoptosis. The doxycycline-induced NF-kappaB activation was not inhibited in HCT116/p53(+/+) cells. Our results demonstrate that NF-kappaB plays an essential role in activation of wild-type p53 tumor suppressor to initiate proapoptotic signaling in response to overgeneration of superoxide. Thus, these findings reveal a mechanism of NF-kappaB-regulated proapoptotic signaling.