The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-α /Sima

Mostrar todas las versiones(3)

The hypoxia-inducible factor (HIF) is a heterodimeric transcription factor composed of a constitutively expressed HIF-β subunit and an oxygen-regulated HIF-α subunit. We have previously defined a hypoxia-inducible transcriptional response in Drosophila melanogaster that is homologous to the mammalia...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Dekanty, A., Lavista-Llanos, S., Irisarri, M., Oldham, S., Wappner, P.
Formato: Artículo publishedVersion
Publicado: 2005
Materias:
Drosphila
Hypoxia-inducible factor (HIF)
Nuclear localization
PI3K pathway
Sima
hypoxia inducible factor 1alpha
hypoxia inducible factor 1beta
insulin
messenger RNA
phosphatidylinositol 3 kinase
phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase
protein kinase B
protein similar
protein tango
transcription factor
transcription factor PAS
unclassified drug
article
cellular distribution
Drosophila
embryo
embryo development
enzyme activation
gene overexpression
immunofluorescence
in vivo study
nonhuman
Northern blotting
polyacrylamide gel electrophoresis
priority journal
protein localization
protein stability
reverse transcription polymerase chain reaction
RNA interference
signal transduction
transcription regulation
upregulation
1-Phosphatidylinositol 3-Kinase
Active Transport, Cell Nucleus
Animals
Aryl Hydrocarbon Receptor Nuclear Translocator
Cell Hypoxia
Cell Line
Cell Nucleus
DNA-Binding Proteins
Dose-Response Relationship, Drug
Drosophila Proteins
Embryo, Nonmammalian
Gene Expression Regulation
Hypoxia-Inducible Factor 1, alpha Subunit
Insulin
Oxygen
Proto-Oncogene Proteins c-akt
RNA
RNA Interference
Signal Transduction
Transcription, Genetic
Drosophila melanogaster
Mammalia
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_00219533_v118_n23_p5431_Dekanty
http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=artiaex&d=paper_00219533_v118_n23_p5431_Dekanty_oai
Aporte de:
Repositorio Digital de la Universidad de Buenos Aires (UBA) de Universidad de Buenos Aires
Descripción
Sumario:The hypoxia-inducible factor (HIF) is a heterodimeric transcription factor composed of a constitutively expressed HIF-β subunit and an oxygen-regulated HIF-α subunit. We have previously defined a hypoxia-inducible transcriptional response in Drosophila melanogaster that is homologous to the mammalian HIF-dependent response. In Drosophila, the bHLH-PAS proteins Similar (Sima) and Tango (Tgo) are the functional homologues of the mammalian HIF-α and HIF-β subunits, respectively. HIF-α/Sima is regulated by oxygen at several different levels that include protein stability and subcellular localization. We show here for the first time that insulin can activate HIF-dependent transcription, both in Drosophila S2 cells and in living Drosophila embryos. Using a pharmacological approach as well as RNA interference, we determined that the effect of insulin on HIF-dependent transcriptional induction is mediated by PI3K-AKT and TOR pathways. We demonstrate that stimulation of the transcriptional response involves upregulation of Sima protein but not sima mRNA. Finally, we have analyzed in vivo the effect of the activation of the PI3K-AKT pathway on the subcellular localization of Sima protein. Overexpression of dAKT and dPDK1 in normoxic embryos provoked a major increase in Sima nuclear localization, mimicking the effect of a hypoxic treatment. A similar increase in Sima nuclear localization was observed in dPTEN homozygous mutant embryos, confirming that activation of the PI3K-AKT pathway promotes nuclear accumulation of Sima protein. We conclude that regulation of HIF-α/Sima by the PI3K-AKT-TOR pathway is a major conserved mode of regulation of the HIF-dependent transcriptional response in Drosophila.

Ejemplares similares