miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga
Cellular and systemic responses to low oxygen levels are principally mediated by Hypoxia Inducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors, whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIFα is hydroxylated by specific proly...
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todo:paper_15537390_v12_n5_p_DeLellaEzcurra2023-10-03T16:25:32Z miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga De Lella Ezcurra, A.L. Bertolin, A.P. Kim, K. Katz, M.J. Gándara, L. Misra, T. Luschnig, S. Perrimon, N. Melani, M. Wappner, P. Fatiga hypoxia inducible factor hypoxia inducible factor 1alpha hypoxia inducible factor 1beta hypoxia inducible factor proline dioxygenase microRNA microRNA 190 Sima transcription factor GAL4 unclassified drug hypoxia inducible factor 1alpha microRNA oxygen procollagen proline 2 oxoglutarate 4 dioxygenase 3' untranslated region Article controlled study Drosophila melanogaster embryo environmental stress enzyme inhibition gene interaction gene overexpression hypoxia lethality loss of function mutation nonhuman oxygen supply phenotype protein degradation protein expression protein function protein stability pupa RNA interference trachea animal biosynthesis cell hypoxia gene expression regulation genetic transcription genetics growth, development and aging human metabolism Animals Cell Hypoxia Drosophila melanogaster Gene Expression Regulation Humans Hypoxia-Inducible Factor 1, alpha Subunit MicroRNAs Oxygen Prolyl Hydroxylases Transcription, Genetic Cellular and systemic responses to low oxygen levels are principally mediated by Hypoxia Inducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors, whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIFα is hydroxylated by specific prolyl-4-hydroxylases, targeting it for proteasomal degradation, while in hypoxia the activity of these hydroxylases decreases due to low oxygen availability, leading to HIFα accumulation and expression of HIF target genes. To identify microRNAs required for maximal HIF activity, we conducted an overexpression screen in Drosophila melanogaster, evaluating the induction of a HIF transcriptional reporter. miR-190 overexpression enhanced HIF-dependent biological responses, including terminal sprouting of the tracheal system, while in miR-190 loss of function embryos the hypoxic response was impaired. In hypoxic conditions, miR-190 expression was upregulated and required for induction of HIF target genes by directly inhibiting the HIF prolyl-4-hydroxylase Fatiga. Thus, miR-190 is a novel regulator of the hypoxia response that represses the oxygen sensor Fatiga, leading to HIFα stabilization and enhancement of hypoxic responses. © 2016 De Lella Ezcurra et al. Fil:Melani, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Wappner, P. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_15537390_v12_n5_p_DeLellaEzcurra |
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Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Fatiga hypoxia inducible factor hypoxia inducible factor 1alpha hypoxia inducible factor 1beta hypoxia inducible factor proline dioxygenase microRNA microRNA 190 Sima transcription factor GAL4 unclassified drug hypoxia inducible factor 1alpha microRNA oxygen procollagen proline 2 oxoglutarate 4 dioxygenase 3' untranslated region Article controlled study Drosophila melanogaster embryo environmental stress enzyme inhibition gene interaction gene overexpression hypoxia lethality loss of function mutation nonhuman oxygen supply phenotype protein degradation protein expression protein function protein stability pupa RNA interference trachea animal biosynthesis cell hypoxia gene expression regulation genetic transcription genetics growth, development and aging human metabolism Animals Cell Hypoxia Drosophila melanogaster Gene Expression Regulation Humans Hypoxia-Inducible Factor 1, alpha Subunit MicroRNAs Oxygen Prolyl Hydroxylases Transcription, Genetic |
| spellingShingle |
Fatiga hypoxia inducible factor hypoxia inducible factor 1alpha hypoxia inducible factor 1beta hypoxia inducible factor proline dioxygenase microRNA microRNA 190 Sima transcription factor GAL4 unclassified drug hypoxia inducible factor 1alpha microRNA oxygen procollagen proline 2 oxoglutarate 4 dioxygenase 3' untranslated region Article controlled study Drosophila melanogaster embryo environmental stress enzyme inhibition gene interaction gene overexpression hypoxia lethality loss of function mutation nonhuman oxygen supply phenotype protein degradation protein expression protein function protein stability pupa RNA interference trachea animal biosynthesis cell hypoxia gene expression regulation genetic transcription genetics growth, development and aging human metabolism Animals Cell Hypoxia Drosophila melanogaster Gene Expression Regulation Humans Hypoxia-Inducible Factor 1, alpha Subunit MicroRNAs Oxygen Prolyl Hydroxylases Transcription, Genetic De Lella Ezcurra, A.L. Bertolin, A.P. Kim, K. Katz, M.J. Gándara, L. Misra, T. Luschnig, S. Perrimon, N. Melani, M. Wappner, P. miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga |
| topic_facet |
Fatiga hypoxia inducible factor hypoxia inducible factor 1alpha hypoxia inducible factor 1beta hypoxia inducible factor proline dioxygenase microRNA microRNA 190 Sima transcription factor GAL4 unclassified drug hypoxia inducible factor 1alpha microRNA oxygen procollagen proline 2 oxoglutarate 4 dioxygenase 3' untranslated region Article controlled study Drosophila melanogaster embryo environmental stress enzyme inhibition gene interaction gene overexpression hypoxia lethality loss of function mutation nonhuman oxygen supply phenotype protein degradation protein expression protein function protein stability pupa RNA interference trachea animal biosynthesis cell hypoxia gene expression regulation genetic transcription genetics growth, development and aging human metabolism Animals Cell Hypoxia Drosophila melanogaster Gene Expression Regulation Humans Hypoxia-Inducible Factor 1, alpha Subunit MicroRNAs Oxygen Prolyl Hydroxylases Transcription, Genetic |
| description |
Cellular and systemic responses to low oxygen levels are principally mediated by Hypoxia Inducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors, whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIFα is hydroxylated by specific prolyl-4-hydroxylases, targeting it for proteasomal degradation, while in hypoxia the activity of these hydroxylases decreases due to low oxygen availability, leading to HIFα accumulation and expression of HIF target genes. To identify microRNAs required for maximal HIF activity, we conducted an overexpression screen in Drosophila melanogaster, evaluating the induction of a HIF transcriptional reporter. miR-190 overexpression enhanced HIF-dependent biological responses, including terminal sprouting of the tracheal system, while in miR-190 loss of function embryos the hypoxic response was impaired. In hypoxic conditions, miR-190 expression was upregulated and required for induction of HIF target genes by directly inhibiting the HIF prolyl-4-hydroxylase Fatiga. Thus, miR-190 is a novel regulator of the hypoxia response that represses the oxygen sensor Fatiga, leading to HIFα stabilization and enhancement of hypoxic responses. © 2016 De Lella Ezcurra et al. |
| format |
JOUR |
| author |
De Lella Ezcurra, A.L. Bertolin, A.P. Kim, K. Katz, M.J. Gándara, L. Misra, T. Luschnig, S. Perrimon, N. Melani, M. Wappner, P. |
| author_facet |
De Lella Ezcurra, A.L. Bertolin, A.P. Kim, K. Katz, M.J. Gándara, L. Misra, T. Luschnig, S. Perrimon, N. Melani, M. Wappner, P. |
| author_sort |
De Lella Ezcurra, A.L. |
| title |
miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga |
| title_short |
miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga |
| title_full |
miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga |
| title_fullStr |
miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga |
| title_full_unstemmed |
miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga |
| title_sort |
mir-190 enhances hif-dependent responses to hypoxia in drosophila by inhibiting the prolyl-4-hydroxylase fatiga |
| url |
http://hdl.handle.net/20.500.12110/paper_15537390_v12_n5_p_DeLellaEzcurra |
| work_keys_str_mv |
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1807323194819870720 |