The regulation of ATF3 gene expression by mitogen-activated protein kinases
The regulation of ATF3 gene expression by mitogen-activated protein kinases
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DOI：
10.1042/bj20061081
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发表时间：
2007-01-15
影响因子：
4.1
通讯作者：
Hai, Tsonwin
中科院分区：
文献类型：
--
作者：
Lu, Dan;Chen, Jingchun;Hai, Tsonwin
ATF3（活化转录因子3）基因编码ATF/CREB （cAMP-response-element-binding protein，反应元件结合蛋白）转录因子家族的一个成员。它的表达受多种信号的诱导，包括应激信号和促进细胞增殖和运动的信号。因此，ATF3基因可以被描述为细胞应对细胞外和/或细胞内变化的“适应性反应”基因。在本研究中，我们证明p38信号通路参与应激信号诱导ATF3。p38上游激酶CA (constitutively active) MKK6 [MAPK (mitogen-activated protein kinase) kinase 6]的异位表达表明p38通路的激活足以诱导ATF3基因的表达。该通路的抑制表明p38通路是诱导ATF3的多种信号所必需的，包括大霉素、IL-1 β（白细胞介素1 β）、TNF α（肿瘤坏死因子α）和H2O2。对内源性ATF3基因的分析表明，至少部分调控在转录水平上。具体来说，CREB，一种已知被p38磷酸化的转录因子，在这种诱导中起作用。有趣的是，ERK（细胞外信号调节激酶）和JNK （c-Jun n -末端激酶）/SAPK（应激激活蛋白激酶）信号通路既不是诱导ATF3的必要条件，也不是诱导ATF3的充分条件。此外，caspase 3激活分析表明，敲除ATF3可降低MKK6（CA）发挥促凋亡作用的能力。综上所述，我们的研究结果表明，一个主要的信号通路p38通路在应激信号诱导ATF3的过程中起着关键作用，而ATF3在介导p38的促凋亡作用中具有重要的功能。
ATF3 (activating transcription factor 3) gene encodes a member of the ATF/CREB (cAMP-response-element-binding protein) family of transcription factors. Its expression is induced by a wide range of signals, including stress signals and signals that promote cell proliferation and motility. Thus the ATF3 gene can be characterized as an 'adaptive response' gene for the cells to cope with extra- and/or intra-cellular changes. In the present study, we demonstrate that the p38 signalling pathway is involved in the induction of ATF3 by stress signals. Ectopic expression of CA (constitutively active) MKK6 [MAPK (mitogen-activated protein kinase) kinase 6], a kinase upstream of p38, indicated that activation of the p38 pathway is sufficient to induce the expression of the ATF3 gene. Inhibition of the pathway indicated that the p38 pathway is necessary for various signals to induce ATF3, including anisomycin, IL-1 beta (interleukin 1 beta), TNF alpha (tumour necrosis factor alpha) and H2O2. Analysis of the endogenous ATF3 gene indicates that the regulation is at least in part at the transcription level. Specifically, CREB, a transcription factor known to be phosphorylated by p38, plays a role in this induction. Interestingly, the ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase)/SAPK (stress-activated protein kinase) signalling pathways are neither necessary nor sufficient to induce ATF3 in the anisomycin stress paradigm. Furthermore, analysis of caspase 3 activation indicated that knocking down ATF3 reduced the ability of MKK6(CA) to exert its pro-apoptotic effect. Taken together, our results indicate that a major signalling pathway, the p38 pathway, plays a critical role in the induction of ATF3 by stress signals, and that ATF3 is functionally important to mediate the pro-apoptotic effects of p38.