MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1alpha in rasV12 upregulation of VEGF.
Oncogenic ras upregulates the expression of VEGF through the activation of the transcriptional enhancer hypoxia inducible factor-1alpha (HIF-1alpha) by a still poorly understood mechanism. Here, we demonstrate that both the Raf/MEK/MAPK and the PI3 kinase/Akt signaling pathways potently and additively stimulate the expression from a hypoxia response element (HRE) within the 5'flanking region of the VEGF promoter. Interestingly, while MAPK appears to specifically upregulate the transactivation activity of HIF-1alpha through direct phosphorylation of its regulatory/inhibitory domain, GSK-3, a downstream target of Akt, directly phosphorylates the HIF-1alpha oxygen-dependent degradation domain. These results suggest a novel mechanism whereby two divergent signaling pathways emerging from Ras may cooperatively but independently regulate the activity of a HIF-1alpha, thereby promoting the expression of a potent angiogenic mediator.
Sodhi
A
A
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, 30 Convent Drive, Bethesda, MD 20892-4330, USA.
Montaner
S
S
Miyazaki
H
H
Gutkind
J S
JS
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014157:Transcription Factors; D015533:Transcriptional Activation; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018631:ras Proteins / Q000502:physiology*
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D018631:ras Proteins