HYPOXIC INDUCTION OF HUMAN VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION THROUGH C-SRC ACTIVATION
HYPOXIC INDUCTION OF HUMAN VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION THROUGH C-SRC ACTIVATION
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DOI：
10.1038/375577a0
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发表时间：
1995-06-15
期刊：
影响因子：
64.8
通讯作者：
SUKHATME, VP
中科院分区：
文献类型：
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作者：
MUKHOPADHYAY, D;TSIOKAS, L;SUKHATME, VP
血管生成通过毛细血管萌芽形成新的微脉管系统，对于肿瘤的发展至关重要(1)。实体瘤的缺氧区域会产生强大且直接作用的血管生成蛋白 VEGF/VPF（血管内皮生长因子/血管通透性因子）(2-6)。我们现在研究缺氧诱导 VEGF 表达的信号转导途径。众所周知，缺氧会诱导酪氨酸激酶级联反应，从而激活苜蓿根瘤菌(7) 中的固氮基因，而酪氨酸激酶的激活对于生长因子和紫外线触发的信号传导至关重要。我们在此表明，金雀异黄酮（一种蛋白酪氨酸激酶抑制剂）可阻断 VEGF 诱导。缺氧会增加 pp60(c-src) 的激酶活性及其对酪氨酸 416 的磷酸化，但不会激活 Fyn 或 Yes。 c-Src 或 Raf-1 的显性失活突变体形式的表达显着降低 VEGF 诱导。尽管 Fyn 存在代偿性激活，但 c-src(-) 细胞中缺氧对 VEGF 的诱导作用受损。我们的结果提供了对缺氧触发的细胞内信号传导的深入了解，将 VEGF 定义为 c-Src 的新下游靶标，并表明 c-Src 在促进血管生成中的作用。
ANGIOGENESIS the formation of new microvasculature by capillary sprouting, is crucial for tumour development(1). Hypoxic regions of solid tumours produce the powerful and directly acting angiogenic protein VEGF/VPF (vascular endothelial growth factor/vascular permeability factor)(2-6). We now investigate the signal transduction pathway involved in hypoxic induction of VEGF expression. Hypoxia is known to induce a tyrosine kinase cascade that results in the activation of nitrogen-fixation genes in Rhizobium meliloti(7), and activation of tyrosine kinases is critical in signalling triggered by growth factors and ultraviolet light. We show here that genistein, an inhibitor of protein tyrosine kinases blocks VEGF induction. Hypoxia increases the kinase activity of pp60(c-src) and its phosphorylation on tyrosine 416 but does not activate Fyn or Yes. Expression of either a dominant-negative mutant form of c-Src or of Raf-1 markedly reduces VEGF induction. VEGF induction by hypoxia in c-src(-) cells is impaired, although there is a compensatory activation of Fyn. Our results provide an insight into hypoxia-triggered intracellular signalling, define VEGF as a new downstream target for c-Src, and suggest a role for c-Src in promoting angiogenesis.