Activating transcription factor 4 is translationally regulated by hypoxic stress
Activating transcription factor 4 is translationally regulated by hypoxic stress
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DOI：
10.1128/mcb.24.17.7469-7482.2004
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发表时间：
2004-09-01
影响因子：
5.3
通讯作者：
Bell, JC
中科院分区：
文献类型：
--
作者：
Blais, JD;Filipenko, V;Bell, JC
低氧应激导致蛋白质合成的快速和持续抑制，其至少部分由内质网（ER）激酶PERK的真核起始因子2 α（eIF 2 α）磷酸化介导。在这里，我们通过微阵列分析的多核糖体结合的RNA在有氧和缺氧的HeLa细胞，一个子集的成绩单在缺氧期间优先翻译，包括激活转录因子4（ATF 4），一个重要的介体的未折叠的蛋白质反应。未折叠蛋白应答过程中mRNA翻译的变化由翻译起始因子eIF 2 α Ser-51的PERK磷酸化介导。类似地，PERK被激活并负责缺氧条件下的翻译调节，同时诱导ATF 4的翻译。GADD 34的C-末端片段组成性去磷酸化eIF 2 α的过表达能够减弱eIF 2 α的磷酸化，并严重抑制响应于缺氧应激的ATF 4的诱导。这些研究证明了ATF 4在低氧应激反应中的重要作用，确定了其诱导途径，并揭示了GADD 34（ATF 4活化的靶点）负调控eIF 2 α介导的翻译抑制。与伴随诱导额外的ER-居民蛋白确定我们的微阵列分析，这项研究表明，ER信号和细胞适应缺氧应激之间的一个重要的综合反应。
Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2alpha at Ser-51. Similarly, PERK is activated and is responsible for translational regulation under hypoxic conditions, while inducing the translation of ATF4. The overexpression of a C-terminal fragment of GADD34 that constitutively dephosphorylates eIF2alpha was able to attenuate the phosphorylation of eIF2alpha and severely inhibit the induction of ATF4 in response to hypoxic stress. These studies demonstrate the essential role of ATF4 in the response to hypoxic stress, define the pathway for its induction, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2alpha-mediated inhibition of translation. Taken with the concomitant induction of additional ER-resident proteins identified by our microarray analysis, this study suggests an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.