Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation

Debabrata Mukhopadhyay, Leonidas Tsiokas, Xiao Mai Zhou, David Foster, Joan S. Brugge, Vikas P. Sukhatme

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523 Scopus citations

Abstract

ANGIOGENESIS, the formation of new microvasculature by capillary sprouting, is crucial for tumour development1. 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 kinase8, blocks VEGF induction. Hypoxia increases the kinase activity of pp60c-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.

Original languageEnglish (US)
Pages (from-to)577-581
Number of pages5
JournalNature
Volume375
Issue number6532
DOIs
StatePublished - Jan 1 1995

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    Mukhopadhyay, D., Tsiokas, L., Zhou, X. M., Foster, D., Brugge, J. S., & Sukhatme, V. P. (1995). Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature, 375(6532), 577-581. https://doi.org/10.1038/375577a0