Dual-specificity phosphatase DUSP1 protects overactivation of hypoxia-inducible factor 1 through inactivating ERK MAPK
Dual-specificity phosphatase DUSP1 protects overactivation of hypoxia-inducible factor 1 through inactivating ERK MAPK
复制标题
双特异性磷酸酶 DUSP1 通过灭活 ERK MAPK 来保护缺氧诱导因子 1 的过度激活。
DOI：
10.1016/j.yexcr.2005.06.022
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发表时间：
2005-10-01
影响因子：
3.7
通讯作者：
Fan, DM
中科院分区：
文献类型：
--
作者：
Liu, CJ;Shi, YQ;Fan, DM
低氧诱导因子1（HIF-1）在控制低氧肿瘤细胞的氧输送和代谢适应低氧条件中起关键作用。HIF-1的激活是由包括丝裂原活化蛋白激酶（MAPK）超家族在内的多种因子启动的。我们以前曾报道过丝裂原活化蛋白激酶磷酸酶DUSP 1（MK-P-1）参与了HIF-1 α亚基磷酸化和HIF-1活性的负调控。然而，MKP-1影响HIF-1活性的分子基础尚不清楚。在本文中，我们表明，缺氧转录诱导MKP-1表达的时间依赖性的方式。同时，缺氧还激活细胞外信号调节激酶（ERK），其活性分别通过MKP-1抑制或MKP-1过表达而增强或降低。我们还表明，MKP-1表达的抑制促进HIF-1 α亚基和p300（HIF-1的共激活因子）之间的相互作用。此外，MKP-1抑制导致HIF-1活性增强，这可以被ERK激酶抑制剂PD 98059抵消。综上所述，本研究结果表明，缺氧诱导的MKP-1通过抑制ERK激酶活性保护HIF-1的过度激活。(c)2005年爱思唯尔公司All rights reserved.
Hypoxia-inducible factor 1 (HIF-1) plays a critical role in controlling oxygen delivery and metabolic adaptation to hypoxic conditions in hypoxic tumor cells. HIF-1 activation is initiated by several factors including mitogen-activated protein kinase (MAPK) superfamily. We have previously reported that mitogen-activated protein kinase phosphatase DUSP1 (MK-P-1) was implicated in the negative regulation of HIF-1 alpha subunit phosphorylation and HIF-1 activity. However, the molecular basis by which MKP-1 influences HIF-1 activity is not clarified. In this paper, we show that hypoxia transcriptionally induces MKP-1 expression in a time-dependent manner. Meanwhile, hypoxia also activates extracellular signal-regulated kinase (ERK) whose activity is enhanced or reduced by MKP-1 suppression or MKP-1 overexpression, respectively. We also show that suppression of MKP-1 expression facilitates the interaction between HIF-1 alpha subunit and p300, a co-activator of HIF-1. Moreover, MKP-1 suppression leads to enhanced HIF-1 activity, which can be counteracted by PD98059, an ERK kinase inhibitor. Taken together, the results presented here suggest that hypoxia-induced MKP-1 protects overactivation of HIF-1 activation through inhibiting ERK kinase activity. (c) 2005 Elsevier Inc. All rights reserved.