p53-mediated induction of Cox-2 counteracts p53-or genotoxic stress-induced apoptosis
p53-mediated induction of Cox-2 counteracts p53-or genotoxic stress-induced apoptosis
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DOI：
10.1093/emboj/cdf591
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发表时间：
2002-11-01
期刊：
影响因子：
11.4
通讯作者：
Lee, SW
中科院分区：
文献类型：
--
作者：
Han, JA;Kim, JI;Lee, SW
确定肿瘤抑制基因P53的转录靶点对于理解其影响细胞结果的机制至关重要。通过表达谱分析，我们鉴定了环氧合酶2(COX-2)，其表达受野生型P53和DNA损伤的诱导。我们还发现，P53诱导的COX-2表达是P53介导的Ras/Raf/MAPK级联反应的结果，显性阴性的RAS或Raf1突变体抑制了对P53的COX-2诱导。此外，P53下游靶基因肝素结合的表皮生长因子样生长因子(HB-EGF)可诱导COX-2的表达，提示COX-2是P53-->；HB-EGF-->；RAS/Raf/MAPK-&GX-2通路的终极效应者。与野生型细胞相比，COX-2基因敲除细胞中P53诱导的细胞凋亡显著增强，提示COX-2对P53诱导的细胞凋亡具有抑制作用。此外，选择性COX-2抑制剂NS-398通过caspase依赖的途径显著增强了遗传毒性应激诱导的几种类型的p53+/+正常人类细胞的凋亡。综上所述，这些结果表明，COX-2是由P53介导的Ras/Raf/ERK级联反应的激活，从而对抗P53介导的细胞凋亡而诱导的。这种抗凋亡作用可能是减轻与P53诱导相关的细胞应激的机制之一。
The identification of transcriptional targets of the tumor suppressor p53 is crucial in understanding mechanisms by which it affects cellular outcomes. Through expression array analysis, we identified cyclooxygenase 2 (Cox-2), whose expression was inducible by wild-type p53 and DNA damage. We also found that p53-induced Cox-2 expression results from p53-mediated activation of the Ras/Raf/MAPK cascade, as demonstrated by suppression of Cox-2 induction in response to p53 by dominant-negative Ras or Raf1 mutants. Furthermore, heparin-binding epidermal growth factor-like growth factor (HB- EGF), a p53 downstream target gene, induced Cox-2 expression, implying that Cox-2 is an ultimate effector in the p53-->HB-EGF-->Ras/Raf/MAPK-->Cox-2 pathway. p53-induced apoptosis was enhanced greatly in Cox-2 knock-out cells as compared with wild-type cells, suggesting that Cox-2 has an abrogating effect on p53-induced apoptosis. Also, a selective Cox-2 inhibitor, NS-398, significantly enhanced genotoxic stress-induced apoptosis in several types of p53+/+ normal human cells, through a caspase-dependent pathway. Together, these results demonstrate that Cox-2 is induced by p53-mediated activation of the Ras/Raf/ERK cascade, counteracting p53-mediated apoptosis. This anti-apoptosis effect may be a mechanism to abate cellular stresses associated with p53 induction.