c-Abl regulates Early Growth Response Protein (EGR1) in response to oxidative stress
c-Abl regulates Early Growth Response Protein (EGR1) in response to oxidative stress
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DOI：
10.1038/sj.onc.1208953
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发表时间：
2005-12
期刊：
影响因子：
8
通讯作者：
Jeremy R Stuart;H. Kawai;Kelvin K. Tsai;E. Chuang;Zhi-Min Yuan
中科院分区：
文献类型：
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作者：
Jeremy R Stuart;H. Kawai;Kelvin K. Tsai;E. Chuang;Zhi-Min Yuan
c-Abl是一种酪氨酸激酶，可以作为细胞生长和凋亡的调节剂响应于应激。使用以诱导方式表达c-Abl的细胞系，我们鉴定了其表达受c-Abl激酶活性调节的基因。芯片分析表明，早期生长反应-1（EGR 1）基因的表达是由c-Abl激酶活性诱导的，这在信息和蛋白水平上得到了证实。启动子定位实验表明，c-Abl利用EGR 1启动子中的三个远端血清反应元件（SRE），这些元件通过促分裂原/细胞外受体激酶（MEK/ERK）信号转导被反式激活。PD 95089是MEK/ERK信号传导的特异性抑制剂，以剂量依赖性方式减弱c-Abl介导的EGR 1表达上调。通过使用有丝分裂原/细胞外激酶的显性阴性突变体获得了类似的结果。值得注意的是，过氧化氢诱导的EGFR 1表达似乎是由c-Abl介导的，因为表达显性阴性c-Abl的细胞和c-Abl−/−鼠胚胎成纤维细胞在过氧化氢诱导的EGFR 1表达中完全缺陷。此外，c-Abl诱导的细胞凋亡被EGR 1活性部分减轻，因为缺乏EGR 1表达的细胞经历c-Abl诱导的细胞凋亡的降低速率。总之，这些结果表明，c-Abl通过MEK/ERK途径在调节对氧化应激的凋亡反应中促进EGR 1的诱导。
c-Abl is a tyrosine kinase that can act as a regulator of cell growth and apoptosis in response to stress. Using cell lines expressing c-Abl in an inducible manner, we identified genes whose expression was regulated by c-Abl kinase activity. Microarray analysis indicated that Early Growth Response-1 (EGR1) gene expression is induced by c-Abl kinase activity, which was confirmed at the message and protein levels. Promoter mapping experiments revealed that c-Abl utilizes three distal serum response elements (SREs) in the EGR1 promoter, which are transactivated by mitogen/extracellular receptor kinase (MEK/ERK) signaling. PD 95089, a specific inhibitor of MEK/ERK signaling, attenuated c-Abl-mediated upregulation of EGR1 expression in a dose-dependent manner. Similar results were obtained by using a dominant-negative mutant of mitogen/extracellular kinase. Significantly, hydrogen peroxide-induced EGR1 expression appears to be mediated by c-Abl, as cells expressing dominant negative c-Abl, and c-Abl−/− murine embryonic fibroblasts, are completely defective in hydrogen peroxide-induced EGR1 expression. In addition, c-Abl-induced apoptosis is partially mitigated by EGR1 activity, as cells devoid of EGR1 expression undergo reduced rates of c-Abl-induced apoptosis. Together, these results indicate that c-Abl promotes the induction of EGR1 through the MEK/ERK pathway in regulating apoptotic response to oxidative stress.