Signaling angiogenesis via p42/p44 MAP kinase and hypoxia
Signaling angiogenesis via p42/p44 MAP kinase and hypoxia
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DOI：
10.1016/s0006-2952(00)00423-8
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发表时间：
2000-10-15
影响因子：
5.8
通讯作者：
Pouysségur, J
中科院分区：
文献类型：
--
作者：
Berra, E;Milanini, J;Pouysségur, J
血管生成与许多病理情况有关。在这项研究中，我们将注意力集中在p42/p44 MAP（丝裂原活化蛋白）激酶和缺氧在血管生成控制中的作用。我们证明p42/p44 MAP激酶通过在三个水平上发挥决定作用在血管生成中起关键作用：1)p42/p44 MAP激酶的持续激活可消除细胞凋亡；ii) p42/p44 MAP激酶活性对于控制融合内皮细胞的增殖和生长停滞至关重要；iii) p42/p44 MAP激酶通过募集VEGF启动子近端区域（-88/-66）的AP-2/Sp1（激活蛋白-2）复合体以及缺氧诱导因子1 α (HIF-1 α)的直接磷酸化来激活VEGF（血管内皮生长因子）的转录，从而促进VEGF（血管内皮生长因子）的表达。HIF-1 α在控制HIF-1活性中起着至关重要的作用，HIF-1介导缺氧诱导的VEGF表达。我们发现氧调节的HIF-1 α蛋白水平不受细胞内定位（细胞核与细胞质）的影响。最后，我们提出了一个模型，该模型表明控制HIF-1 α和HIF-1依赖性基因表达的自调节反馈机制。生物化学药学60；8:1171 - 1178, 2000。(C) 2000 Elsevier Science Inc.；
Angiogenesis is associated with a number of pathological situations. In this study, we have focused our attention on the role of p42/p44 MAP (mitogen-activated protein) kinases and hypoxia in the control of angiogenesis. We demonstrate that p42/p44 MAP kinases play a pivotal role in angiogenesis by exerting a determinant action at three levels: i) persistent activation of p42/p44 MAP kinases abrogates apoptosis; ii) p42/p44 MAP kinase activity is critical for controlling proliferation and growth arrest of confluent endothelial cells; and iii) p42/p44 MAP kinases promote VEGF (vascular endothelial growth factor) expression by activating its transcription via recruitment of the AP-2/Sp1 (activator protein-2) complex on the proximal region (-88/-66) of the VEGF promoter and by direct phosphorylation of hypoxia-inducible factor 1 alpha (HIF-1 alpha). HIF-1 alpha plays a crucial role in the control of HIF-1 activity, which mediates hypoxia-induced VEGF expression. We show that oxygen-regulated HIF-1 alpha protein levels are not affected by intracellular localisation (nucleus versus cytoplasm). Finally, we propose a model which suggests an autoregulatory feedback mechanism controlling HIF-1 alpha and therefore HIF-1 dependent gene expression. BIOCHEM PHARMACOL 60;8:1171-1178, 2000. (C) 2000 Elsevier Science Inc.