Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2007, PMID: 17502379

Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif.

Land, Stephen C; Tee, Andrew R

Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF)-mediated transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor (VEGF)-A secretion during hypoxia, which is reversed with rapamycin. Mutants of Rheb, which do not bind guanine nucleotide (D60K, D60V, N119I, and D122N) and are unable to activate mTOR, inhibit the activity of HIF when overexpressed. We show that regulatory associated protein of mTOR (Raptor) interacts with HIF1alpha and requires an mTOR signaling (TOS) motif located in the N terminus of HIF1alpha. Furthermore, a mutant of HIF1alpha lacking this TOS motif dominantly impaired HIF activity during hypoxia and was unable to bind to the co-activator CBP/p300. Rapamycin treatments do not affect the stability of HIF1alpha and modulate HIF activity via a Von Hippel-Lindau (VHL)-independent mechanism. We demonstrate that the high levels of HIF activity in cells devoid of TSC2 can be reversed by treatments with rapamycin or the readdition of TSC2. Our work explains why human cancers with aberrant mTOR signaling are prone to angiogenesis and suggests that inhibition of mTOR with rapamycin might be a suitable therapeutic strategy.

Diseases/Pathways annotated by Medline MESH: Neoplasms, Neovascularization, Pathologic
Document information provided by NCBI PubMed

Text Mining Data

Hypoxia-inducible factor 1alpha → mammalian target of rapamycin (mTOR): " Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif "

Ras homologue enriched in brain (Rheb) → mTOR: " Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor ( VEGF ) -A secretion during hypoxia, which is reversed with rapamycin "

vascular endothelial growth factor → Ras homologue enriched in brain (Rheb): " Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor ( VEGF ) -A secretion during hypoxia, which is reversed with rapamycin "

vascular endothelial growth factor → mTOR: " Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor ( VEGF ) -A secretion during hypoxia, which is reversed with rapamycin "

HIF1alpha → Ras homologue enriched in brain (Rheb): " Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor ( VEGF ) -A secretion during hypoxia, which is reversed with rapamycin "

HIF1alpha → mTOR: " Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor ( VEGF ) -A secretion during hypoxia, which is reversed with rapamycin "

Manually curated Databases

  • IRef Biogrid Interaction: HIF1A — RPTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: EIF4EBP1 — RPTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: EP300 — HIF1A (physical association, affinity chromatography technology)
  • IRef Innatedb Interaction: HIF1A — EP300 (unknown, -)
In total, 3 gene pairs are associated to this article in curated databases