MicroRNA-155 promotes resolution of hypoxia-inducible factor 1α activity during prolonged hypoxia

Ulrike Bruning, Luca Cerone, Zoltan Neufeld, Susan F. Fitzpatrick, Alex Cheong, Carsten C. Scholz, David A. Simpson, Martin O. Leonard, Murtaza M. Tambuwala, Eoin P. Cummins, Cormac T. Taylor

Research output: Contribution to journalArticle

Abstract

The hypoxia-inducible factor (HIF) is a key regulator of the transcriptional response to hypoxia. While the mechanism underpinning HIF activation is well understood, little is known about its resolution. Both the protein and the mRNA levels of HIF-1a (but not HIF-2a) were decreased in intestinal epithelial cells exposed to prolonged hypoxia. Coincident with this, microRNA (miRNA) array analysis revealed multiple hypoxiainducible miRNAs. Among these was miRNA-155 (miR-155), which is predicted to target HIF-1a mRNA. We confirmed the hypoxic upregulation of miR-155 in cultured cells and intestinal tissue from mice exposed to hypoxia. Furthermore, a role for HIF-1a in the induction of miR-155 in hypoxia was suggested by the identification of hypoxia response elements in the miR-155 promoter and confirmed experimentally. Application of miR-155 decreased the HIF-1a mRNA, protein, and transcriptional activity in hypoxia, and neutralization of endogenous miR-155 reversed the resolution of HIF-1a stabilization and activity. Based on these data and a mathematical model of HIF-1a suppression by miR-155, we propose that miR-155 induction contributes to an isoform-specific negative-feedback loop for the resolution of HIF-1a activity in cells exposed to prolonged hypoxia, leading to oscillatory behavior of HIF-1a-dependent transcription.
Original languageEnglish
Pages (from-to)4087-4096
Number of pages10
JournalMolecular and Cellular Biology
Volume31
Issue number19
Early online date1 Aug 2011
DOIs
Publication statusPublished - Oct 2011

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Hypoxia-Inducible Factor 1
MicroRNAs
Hypoxia
Messenger RNA

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Bruning, U., Cerone, L., Neufeld, Z., Fitzpatrick, S. F., Cheong, A., Scholz, C. C., ... Taylor, C. T. (2011). MicroRNA-155 promotes resolution of hypoxia-inducible factor 1α activity during prolonged hypoxia. Molecular and Cellular Biology, 31(19), 4087-4096. https://doi.org/10.1128/MCB.01276-10
Bruning, Ulrike ; Cerone, Luca ; Neufeld, Zoltan ; Fitzpatrick, Susan F. ; Cheong, Alex ; Scholz, Carsten C. ; Simpson, David A. ; Leonard, Martin O. ; Tambuwala, Murtaza M. ; Cummins, Eoin P. ; Taylor, Cormac T. / MicroRNA-155 promotes resolution of hypoxia-inducible factor 1α activity during prolonged hypoxia. In: Molecular and Cellular Biology. 2011 ; Vol. 31, No. 19. pp. 4087-4096.
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Bruning, U, Cerone, L, Neufeld, Z, Fitzpatrick, SF, Cheong, A, Scholz, CC, Simpson, DA, Leonard, MO, Tambuwala, MM, Cummins, EP & Taylor, CT 2011, 'MicroRNA-155 promotes resolution of hypoxia-inducible factor 1α activity during prolonged hypoxia', Molecular and Cellular Biology, vol. 31, no. 19, pp. 4087-4096. https://doi.org/10.1128/MCB.01276-10

MicroRNA-155 promotes resolution of hypoxia-inducible factor 1α activity during prolonged hypoxia. / Bruning, Ulrike; Cerone, Luca; Neufeld, Zoltan; Fitzpatrick, Susan F.; Cheong, Alex; Scholz, Carsten C.; Simpson, David A.; Leonard, Martin O.; Tambuwala, Murtaza M.; Cummins, Eoin P.; Taylor, Cormac T.

In: Molecular and Cellular Biology, Vol. 31, No. 19, 10.2011, p. 4087-4096.

Research output: Contribution to journalArticle

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T1 - MicroRNA-155 promotes resolution of hypoxia-inducible factor 1α activity during prolonged hypoxia

AU - Bruning, Ulrike

AU - Cerone, Luca

AU - Neufeld, Zoltan

AU - Fitzpatrick, Susan F.

AU - Cheong, Alex

AU - Scholz, Carsten C.

AU - Simpson, David A.

AU - Leonard, Martin O.

AU - Tambuwala, Murtaza M.

AU - Cummins, Eoin P.

AU - Taylor, Cormac T.

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N2 - The hypoxia-inducible factor (HIF) is a key regulator of the transcriptional response to hypoxia. While the mechanism underpinning HIF activation is well understood, little is known about its resolution. Both the protein and the mRNA levels of HIF-1a (but not HIF-2a) were decreased in intestinal epithelial cells exposed to prolonged hypoxia. Coincident with this, microRNA (miRNA) array analysis revealed multiple hypoxiainducible miRNAs. Among these was miRNA-155 (miR-155), which is predicted to target HIF-1a mRNA. We confirmed the hypoxic upregulation of miR-155 in cultured cells and intestinal tissue from mice exposed to hypoxia. Furthermore, a role for HIF-1a in the induction of miR-155 in hypoxia was suggested by the identification of hypoxia response elements in the miR-155 promoter and confirmed experimentally. Application of miR-155 decreased the HIF-1a mRNA, protein, and transcriptional activity in hypoxia, and neutralization of endogenous miR-155 reversed the resolution of HIF-1a stabilization and activity. Based on these data and a mathematical model of HIF-1a suppression by miR-155, we propose that miR-155 induction contributes to an isoform-specific negative-feedback loop for the resolution of HIF-1a activity in cells exposed to prolonged hypoxia, leading to oscillatory behavior of HIF-1a-dependent transcription.

AB - The hypoxia-inducible factor (HIF) is a key regulator of the transcriptional response to hypoxia. While the mechanism underpinning HIF activation is well understood, little is known about its resolution. Both the protein and the mRNA levels of HIF-1a (but not HIF-2a) were decreased in intestinal epithelial cells exposed to prolonged hypoxia. Coincident with this, microRNA (miRNA) array analysis revealed multiple hypoxiainducible miRNAs. Among these was miRNA-155 (miR-155), which is predicted to target HIF-1a mRNA. We confirmed the hypoxic upregulation of miR-155 in cultured cells and intestinal tissue from mice exposed to hypoxia. Furthermore, a role for HIF-1a in the induction of miR-155 in hypoxia was suggested by the identification of hypoxia response elements in the miR-155 promoter and confirmed experimentally. Application of miR-155 decreased the HIF-1a mRNA, protein, and transcriptional activity in hypoxia, and neutralization of endogenous miR-155 reversed the resolution of HIF-1a stabilization and activity. Based on these data and a mathematical model of HIF-1a suppression by miR-155, we propose that miR-155 induction contributes to an isoform-specific negative-feedback loop for the resolution of HIF-1a activity in cells exposed to prolonged hypoxia, leading to oscillatory behavior of HIF-1a-dependent transcription.

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