Post-Transcriptional Control of the Hypoxic Response by RNA-Binding Proteins and MicroRNAs

Gorospe, Myriam; Tominaga, Kikuo; Wu, Xue; Fähling, Michael; Ivan, Mircea

doi:10.3389/fnmol.2011.00007

Cited by 102 publications

(93 citation statements)

References 174 publications

(248 reference statements)

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“…2C), a transcript that is known to be stabilized during iron deprivation (32). DFO treatment also led to an increase in the stability of Hk2 and Slc2a1, which encode proteins involved in glucose metabolism, and whose expression can be influenced post-transcriptionally during nutrient stress via RNA-binding factors (33)(34)(35). Importantly, the half-lives of OxPhos transcripts determined from our analyses were similar to those from a global analysis of transcript turnover (36).…”

Section: Resultssupporting

confidence: 59%

“…DMOG treatment caused increased levels of transcripts encoding glucose metabolic proteins (Fig. 7A), likely via HIF-1␣ stabilization (38) or posttranscriptional regulation (33,35), but did not affect OxPhos-encoding transcripts (Fig. 7B), suggesting that demethylation is not the main regulator of this FIGURE 5.…”

Section: Iron Deprivation Decreases Histone Acetylation At Nuclear Dnmentioning

confidence: 99%

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Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis

Rensvold

Krautkramer

Dowell

et al. 2016

Journal of Biological Chemistry

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Mitochondria are essential organelles that adapt to stress and environmental changes. Among the nutrient signals that affect mitochondrial form and function is iron, whose depletion initiates a rapid and reversible decrease in mitochondrial biogenesis through unclear means. Here we demonstrate that, unlike the canonical iron-induced alterations to transcript stability, loss of iron dampens the transcription of genes encoding mitochondrial proteins with no change to transcript half-life. Using mass spectrometry, we demonstrate that these transcriptional changes are accompanied by dynamic alterations to histone acetylation and methylation levels that are largely reversible upon readministration of iron. Moreover, histone deacetylase inhibition abrogates the decreased histone acetylation observed upon iron deprivation and restores normal transcript levels at genes encoding mitochondrial proteins. Collectively, we demonstrate that deprivation of an essential nutrient induces transcriptional repression of organellar biogenesis involving epigenetic alterations.

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Section: Resultssupporting

confidence: 59%

Section: Iron Deprivation Decreases Histone Acetylation At Nuclear Dnmentioning

confidence: 99%

Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis

Rensvold

Krautkramer

Dowell

et al. 2016

Journal of Biological Chemistry

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“…These processes are modulated efficiently by both RNA-binding proteins (RBPs) and microRNAs (miRNAs) (20)(21)(22). RBPs associate with specific sequences within the 59-or 39-untranslated region (UTR) of many mRNAs, and this association either increases or decreases mRNA stability or translation depending on the particular mRNA sequence and cellular stimuli (20).…”

Section: Metabolismmentioning

confidence: 99%

RNA-Binding Protein PTB and MicroRNA-221 Coregulate AdipoR1 Translation and Adiponectin Signaling

et al. 2014

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Adiponectin receptor 1 (AdipoR1) mediates adiponectin's pleiotropic effects in muscle and liver and plays an important role in the regulation of insulin resistance and diabetes. Here, we demonstrate a pivotal role for microRNA-221 (miR-221) and the RNA-binding protein polypyrimidine tract-binding protein (PTB) in posttranscriptional regulation of AdipoR1 during muscle differentiation and in obesity. RNA-immunoprecipitation and luciferase reporter assays illustrated that both PTB and miR-221 bind AdipoR1-39UTR and cooperatively inhibit AdipoR1 translation. Depletion of PTB or miR-221 increased, while overexpression of these factors decreased, AdipoR1 protein synthesis in both muscle and liver cells. During myogenesis, downregulation of PTB and miR-221 robustly induced AdipoR1 translation, providing a mechanism for enhanced AdipoR1 protein expression and activation in differentiated muscle cells. In addition, since both PTB and miR-221 are upregulated in liver and muscle of genetic and dietary mouse models of obesity, this novel translational mechanism may be at least partly responsible for the reduction in AdipoR1 protein levels in obesity. These findings highlight the importance of translational control in regulating AdipoR1 protein expression and adiponectin signaling. Given that adiponectin is reduced in obesity, induction of AdipoR1 could potentially enhance adiponectin beneficial effects and ameliorate insulin resistance and diabetes. Adiponectin, an adipocyte-derived abundant plasma protein (1-4) with insulin-sensitizing and antiinflammatory properties, gained recognition as a potential mediator between obesity, insulin resistance, and diabetes (5): Adiponectin levels are reduced in obesity (1), and mice lacking adiponectin develop insulin resistance, glucose intolerance, hyperglycemia, and hypertension-all characteristics of the metabolic syndrome (5,6). Adiponectin's biological effects depend not only on the relative circulating concentrations of the hormone but also on the expression level and function of its receptors (5,7-9). To date, two receptors for adiponectin have been identified (AdipoR1 and AdipoR2), which mediate adiponectin pleoitropic effects (10). Downregulation of the receptors in obesity is involved in the development of insulin resistance and diabetes (11).Skeletal muscle and liver are important targets of adiponectin and its receptors in the regulation of energy metabolism (12). Adiponectin, through AdipoR1, METABOLISMactivates AMP-activated protein kinase (AMPK) in vivo and in vitro, which increases fatty acid oxidation and glucose utilization and leads to an improvement in insulin sensitivity (10,11,(13)(14)(15). Recently, overexpression of AdipoR1 in rat skeletal muscle was shown to enhance insulin sensitivity in vivo through phosphatidylinositol 3-kinase-and AMPK-signaling pathways (16). In addition, specific deletion of AdipoR1 in mouse skeletal muscle demonstrated that AdipoR1 is involved in the regulation of Ca 2+ signaling, peroxisome proliferator-activated receptor g coactivat...

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“…miR-210 is considered a prototypical hypoxia-induced miRNA, as it has been shown to be consistently upregulated in different cell types under low oxygen tension, in an HIF-dependent manner (Chan and Loscalzo, 2010;Huang et al, 2010;Gorospe et al, 2011). In HEK 293A cells, miR- Fig.…”

Section: Mirnas Participate In Negative and Positive Feedback Loops Tmentioning

confidence: 99%

Robustness of the hypoxic response: Another job for miRNAs?

Ezcurra

Bertolin

Melani

et al. 2012

Developmental Dynamics

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Living organisms are constantly exposed to environmental and genetic perturbations. Biological robustness enables these organisms to maintain their functional stability in the presence of external or internal changes. It has been proposed that microRNAs (miRNAs), small non-coding regulatory RNAs, contribute to robustness of gene regulatory networks. The hypoxic response is a major and well-characterized example of a cellular and systemic response to environmental stress that needs to be robust. miRNAs regulate the response to hypoxia, both at the level of the main transcription factor that mediates this response, the hypoxia-inducible factor (HIF), and at the level of one of the most important systemic outcomes of the response: angiogenesis. In this review, we will take the hypoxic response as a paradigm of miRNAs participating in circuits that provide robustness to biological responses.

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Post-Transcriptional Control of the Hypoxic Response by RNA-Binding Proteins and MicroRNAs

Cited by 102 publications

References 174 publications

Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis

Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis

RNA-Binding Protein PTB and MicroRNA-221 Coregulate AdipoR1 Translation and Adiponectin Signaling

Robustness of the hypoxic response: Another job for miRNAs?

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