MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1α in rasV12 upregulation of VEGF
MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1α in rasV12 upregulation of VEGF
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DOI：
10.1006/bbrc.2001.5532
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发表时间：
2001-09-14
影响因子：
3.1
通讯作者：
Gutkind, JS
中科院分区：
文献类型：
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作者：
Sodhi, A;Montaner, S;Gutkind, JS
致癌ras通过激活转录增强子缺氧诱导因子-1 α（HIF-1 α）上调VEGF的表达，其机制仍知之甚少。在这里，我们证明了Raf/MEK/MAPK和PI 3激酶/Akt信号通路都有效地和相加地刺激VEGF启动子5 '侧翼区域内的缺氧反应元件（HRE）的表达。有趣的是，虽然MAPK似乎通过其调节/抑制结构域的直接磷酸化特异性上调HIF-1 α的反式激活活性，但Akt的下游靶标GSK-3直接磷酸化HIF-1 α氧依赖性降解结构域。这些结果表明，一种新的机制，其中两个不同的信号通路出现Ras可能合作，但独立地调节HIF-1 α的活性，从而促进表达的一个有效的血管生成介质。
Oncogenic ras upregulates the expression of VEGF through the activation of the transcriptional enhancer hypoxia inducible factor-1 alpha (HIF-1 alpha) by a still poorly understood mechanism. Here, we demonstrate that both the Raf/MEK/MAPK and the PI3 kinase/Akt signaling pathways potently and additively stimulate the expression from a hypoxia response element (HRE) within the 5'flanking region of the VEGF promoter. Interestingly, while MAPK appears to specifically upregulate the transactivation activity of HIF-1 alpha through direct phosphorylation of its regulatory/inhibitory domain, GSK-3, a downstream target of Akt, directly phosphorylates the HIF-1 alpha oxygen-dependent degradation domain. These results suggest a novel mechanism whereby two divergent signaling pathways emerging from Ras may cooperatively but independently regulate the activity of a HIF-1 alpha, thereby promoting the expression of a potent angiogenic mediator.