Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments - A candidate MKP for the inactivation of hypoxia-inducible stress-activated protein kinase/c-Jun N-terminal protein kinase activity
Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments - A candidate MKP for the inactivation of hypoxia-inducible stress-activated protein kinase/c-Jun N-terminal protein kinase activity
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DOI：
10.1074/jbc.274.18.12890
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发表时间：
1999-04-30
影响因子：
4.8
通讯作者：
Stork, PJS
中科院分区：
文献类型：
--
作者：
Laderoute, KR;Mendonca, HL;Stork, PJS
病理生理性缺氧是实体瘤和其他病理条件下基因表达的重要调节剂。我们观察到缺氧肿瘤细胞中c-jun原癌基因的转录激活与ATF 2转录因子的磷酸化相关。这一发现表明，传递到c-jun的缺氧信号涉及靶向AP-1复合物的蛋白激酶（c-Jun和ATF 2），其结合到其启动子区域。能够激活c-jun表达的应激诱导蛋白激酶包括应激激活蛋白激酶/c-Jun N末端蛋白激酶（SAPK/JNK）和信号分子的丝裂原激活蛋白激酶（MAPK）超家族的p38成员。为了探讨MAPK在肿瘤缺氧对c-jun表达的调节中的作用，我们研究了SAPK/JNKs在SiHa人鳞癌细胞中的活化。在这里，我们描述了瞬时激活的SAPK/JNKs肿瘤样缺氧，并同时转录激活MKP-1，应激诱导的成员MAPK磷酸酶（MKP）家族的双特异性蛋白酪氨酸磷酸酶。MKP-1拮抗SAPK/JNK激活响应于不同的环境胁迫。总之，这些发现将MKP-1鉴定为低氧应答基因，并表明在肿瘤微环境中SAPK/JNK活性的调节中起关键作用。
Pathophysiological hypoxia is an important modulator of gene expression in solid tumors and other pathologic conditions. We observed that transcriptional activation of the c-jun proto oncogene in hypoxic tumor cells correlates with phosphorylation of the ATF2 transcription factor. This finding suggested that hypoxic signals transmitted to c-jun involve protein kinases that target AP-1 complexes (c-Jun and ATF2) that bind to its promoter region, Stress-inducible protein kinases capable of activating c-jun expression include stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and p38 members of the mitogen-activated protein kinase (MAPK) superfamily of signaling molecules. To investigate the potential role of MAPKs in the regulation of c-jun by tumor hypoxia, we focused on the activation SAPK/JNKs in SiHa human squamous carcinoma cells. Here, we describe the transient activation of SAPK/JNKs by tumor-like hypoxia, and the concurrent transcriptional activation of MKP-1, a stress-inducible member of the MAPK phosphatase (MKP) family of dual specificity protein-tyrosine phosphatases. MKP-1 antagonizes SAPK/JNK activation in response to diverse environmental stresses. Together, these findings identify MKP-1 as a hypoxia-responsive gene and suggest a critical role in the regulation of SAPK/JNK activity in the tumor microenvironment.