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 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 localization (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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Review
MeSH terms
-
Animals
-
Cell Survival / physiology
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / physiology
-
Endothelial Growth Factors / biosynthesis
-
Endothelial Growth Factors / genetics
-
Endothelium / enzymology
-
Gene Expression / physiology
-
Humans
-
Hypoxia / physiopathology*
-
Hypoxia-Inducible Factor 1
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
Lymphokines / biosynthesis
-
Lymphokines / genetics
-
Mitogen-Activated Protein Kinase 1 / physiology*
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinases / physiology*
-
Neovascularization, Pathologic / physiopathology*
-
Nuclear Proteins / genetics
-
Nuclear Proteins / physiology
-
Oxygen / metabolism*
-
Promoter Regions, Genetic / genetics
-
Signal Transduction
-
Transcription Factors*
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factors
Substances
-
DNA-Binding Proteins
-
Endothelial Growth Factors
-
HIF1A protein, human
-
Hypoxia-Inducible Factor 1
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
Lymphokines
-
Nuclear Proteins
-
Transcription Factors
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factors
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinases
-
Oxygen