A. Sodhi et al., MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1 alpha in rasV12 upregulation of VEGF, BIOC BIOP R, 287(1), 2001, pp. 292-300
Citations number
29
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Oncogenic ras upregulates the expression of VEGF through the activation of
the transcriptional enhancer hypoxia inducible factor-1 alpha (HIF-1 alpha)
by a still poorly understood mechanism. Here, we demonstrate that both the
Raf/MEK/MAPK and the PI3 kinase/Akt signaling pathways potently and additi
vely stimulate the expression from a hypoxia response element (HRE) within
the 5'flanking region of the VEGF promoter. Interestingly, while MAPK appea
rs to specifically upregulate the transactivation activity of HIF-1 alpha t
hrough direct phosphorylation of its regulatory/inhibitory domain, GSK-3, a
downstream target of Akt, directly phosphorylates the HIF-1 alpha oxygen-d
ependent degradation domain. These results suggest a novel mechanism whereb
y two divergent signaling pathways emerging from Ras may cooperatively but
independently regulate the activity of a HIF-1 alpha, thereby promoting the
expression of a potent angiogenic mediator.