Emmanuel Gothié

Publications (2)4.7 Total impact

• Article: Signaling angiogenesis via p42/p44 MAP kinase and hypoxia

  Edurne Berra, Julie Milanini, Darren E Richard, Maude Le Gall, Francesc Viñals, Emmanuel Gothié, Danièle Roux, Gilles Pagès, Jacques Pouysségur
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  ABSTRACT: 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 1α (HIF-1α). HIF-1α plays a crucial role in the control of HIF-1 activity, which mediates hypoxia-induced VEGF expression. We show that oxygen-regulated HIF-1α protein levels are not affected by intracellular localization (nucleus versus cytoplasm). Finally, we propose a model which suggests an autoregulatory feedback mechanism controlling HIF-1α and therefore HIF-1-dependent gene expression.
  Biochemical Pharmacology 11/2000; · 4.70 Impact Factor
• Article: HIF-1-dependent transcriptional activity is required for oxygen-mediated HIF-1α degradation

  Edurne Berra, Darren E Richard, Emmanuel Gothié, Jacques Pouysségur
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  ABSTRACT: Hypoxia-inducible factor-1α (HIF-1α) plays a central role in oxygen homeostasis. In normoxia, HIF-1α is a short lived protein, whereas hypoxia rapidly increases HIF-1α protein levels by relaxing its ubiquitin–proteasome-dependent degradation. In this study, we show that the p42/p44 MAP kinase cascade, known to phosphorylate HIF-1α, does not modulate the degradation/stabilization profile of HIF-1α. However, we present evidence that the rate of HIF-1α degradation depends on the duration of hypoxic stress. We demonstrate that degradation of HIF-1α is suppressed by: (i) inhibiting general transcription with actinomycin D or (ii) specifically blocking HIF-1-dependent transcriptional activity. In keeping with these findings, we postulate that HIF-1α is targetted to the proteasome via a HIF-1α proteasome targetting factor (HPTF) which expression is directly under the control of HIF-1-mediated transcriptional activity. Although HPTF is not yet molecularly identified, it is clearly distinct from the von Hippel–Lindau protein (pVHL).
  FEBS Letters.