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Functional Importance of Dicer Protein in the Adaptive Cellular Response to Hypoxia

The Journal of biological chemistry, 2012-08, Vol.287 (34), p.29003-29020 [Peer Reviewed Journal]

2012 © 2012 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2012 by The American Society for Biochemistry and Molecular Biology, Inc. 2012 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M112.373365 ;PMID: 22745131

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Title:
Functional Importance of Dicer Protein in the Adaptive Cellular Response to Hypoxia
Author: Ho, J.J.David ; Metcalf, Julie L. ; Yan, Matthew S. ; Turgeon, Paul J. ; Wang, Jenny Jing ; Chalsev, Maria ; Petruzziello-Pellegrini, Tania N. ; Tsui, Albert K.Y. ; He, Jeff Z. ; Dhamko, Helena ; Man, H.S.Jeffrey ; Robb, G.Brett ; Teh, Bin T. ; Ohh, Michael ; Marsden, Philip A.
Subjects: Adaptation, Physiological - physiology ; Basic Helix-Loop-Helix Transcription Factors - biosynthesis ; Basic Helix-Loop-Helix Transcription Factors - genetics ; Cell Hypoxia ; DEAD-box RNA Helicases - biosynthesis ; DEAD-box RNA Helicases - genetics ; Dicer ; Endothelial Cell ; Endothelium ; Endothelium, Vascular - cytology ; Endothelium, Vascular - enzymology ; Gene Expression Regulation, Enzymologic - physiology ; Gene Regulation ; Glucose Transporter Type 1 - biosynthesis ; Glucose Transporter Type 1 - genetics ; Hep G2 Cells ; Human Umbilical Vein Endothelial Cells ; Humans ; Hypoxia ; Hypoxia-inducible Factor (HIF) ; Membrane Proteins - biosynthesis ; Membrane Proteins - genetics ; MicroRNA ; MicroRNAs - biosynthesis ; MicroRNAs - genetics ; Molecular Biology ; Molecular Cell Biology ; Oxygen - metabolism ; Proto-Oncogene Proteins - biosynthesis ; Proto-Oncogene Proteins - genetics ; Ribonuclease III - biosynthesis ; Ribonuclease III - genetics ; Tumor Suppressor Proteins - biosynthesis ; Tumor Suppressor Proteins - genetics ; Vascular Endothelial Growth Factor A - biosynthesis ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor Receptor-1 - biosynthesis ; Vascular Endothelial Growth Factor Receptor-1 - genetics ; Vascular Endothelial Growth Factor Receptor-2 - biosynthesis ; Vascular Endothelial Growth Factor Receptor-2 - genetics ; Von Hippel-Lindau Tumor Suppressor Protein - genetics ; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
Is Part Of: The Journal of biological chemistry, 2012-08, Vol.287 (34), p.29003-29020
Description: The processes by which cells sense and respond to ambient oxygen concentration are fundamental to cell survival and function, and they commonly target gene regulatory events. To date, however, little is known about the link between the microRNA pathway and hypoxia signaling. Here, we show in vitro and in vivo that chronic hypoxia impairs Dicer (DICER1) expression and activity, resulting in global consequences on microRNA biogenesis. We show that von Hippel-Lindau-dependent down-regulation of Dicer is key to the expression and function of hypoxia-inducible factor α (HIF-α) subunits. Specifically, we show that EPAS1/HIF-2α is regulated by the Dicer-dependent microRNA miR-185, which is down-regulated by hypoxia. Full expression of hypoxia-responsive/HIF target genes in chronic hypoxia (e.g. VEGFA, FLT1/VEGFR1, KDR/VEGFR2, BNIP3L, and SLC2A1/GLUT1), the function of which is to regulate various adaptive responses to compromised oxygen availability, is also dependent on hypoxia-mediated down-regulation of Dicer function and changes in post-transcriptional gene regulation. Therefore, functional deficiency of Dicer in chronic hypoxia is relevant to both HIF-α isoforms and hypoxia-responsive/HIF target genes, especially in the vascular endothelium. These findings have relevance to emerging therapies given that we show that the efficacy of RNA interference under chronic hypoxia, but not normal oxygen availability, is Dicer-dependent. Collectively, these findings show that the down-regulation of Dicer under chronic hypoxia is an adaptive mechanism that serves to maintain the cellular hypoxic response through HIF-α- and microRNA-dependent mechanisms, thereby providing an essential mechanistic insight into the oxygen-dependent microRNA regulatory pathway. Background: Functional relationships between the microRNA and cellular hypoxia response pathways are unknown. Results: Dicer is down-regulated in chronic hypoxia; this mechanism maintains the induction of hypoxia-inducible factor-α subunits and hypoxia-responsive genes. Conclusion: Loss of Dicer-dependent microRNA regulation is important for maintaining the concerted cellular response to hypoxia. Significance: Altogether, we provide a newer perspective into the post-transcriptional pathways that regulate the cellular hypoxic response.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.M112.373365
PMID: 22745131
Source: Open Access: PubMed Central
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Functional Importance of Dicer Protein in the Adaptive Cellular Response to Hypoxia

2012 © 2012 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2012 by The American Society for Biochemistry and Molecular Biology, Inc. 2012 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M112.373365 ;PMID: 22745131

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