Protein kinases and the Hypoxia-Inducible Factor-1, two switches in angiogenesis

N.   M.   Mazure; M.   C.   Brahimi-Horn; J.      Pouysségur

Abstract

In the last few decades it has become clear that detailed understanding of the mechanisms of angiogenesis, a process leading to growth of new blood vessels, should lead to improved treatment of diseases such as ischemic disorders and cancer where neovascularization is impaired or activated, respectively. In this review, we will outline some of our recent findings concerning the regulation of the vascular endothelial growth factor (VEGF), a key player in angiogenesis and one of its transcription factors, the hypoxia-inducible factor-1 (HIF-1) a master gene product driving adaptation to hypoxia. We will discuss the observation that growth factors and oncogenic transformation via the mitogen-activated protein kinases p42 / p44 MAPKs not only activate the VEGF promoter through the Sp1 / AP-2 transcriptional factor complex but also phosphorylate HIF-1α leading in turn to enhance HIF-1 dependent transcriptional activation of VEGF. The stress-activated protein kinases (SAPK) also contribute to angiogenesis by stabilizing VEGF mRNA. Finally, we will present recent advances into oxygen-sensing, in particular the HIF-hydroxylases that govern HIF-1α instability (PHD2) or inactivation (FIH-1). The revelation of these oxygen sensors has provided pharmacologists with new molecular targets for the development of novel therapies to control angiogenesis either positively or negatively.

Keywords: angiogenesis, asparagyl hydroxylase, inhibiting hypoxia-inducible factor-1, hypoxia-inducible factor-1, mitogen-activated protein kinase, prolyl-4-hydroxylase, vascular endothelial growth factor

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