MicroRNA Functions in Stress Responses

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Molecular cell (Impact Factor: 14.02). 10/2010; 40(2):205-15. DOI: 10.1016/j.molcel.2010.09.027
Source: PubMed


MicroRNAs (miRNAs) are a class of ∼22 nucleotide short noncoding RNAs that play key roles in fundamental cellular processes, including how cells respond to changes in environment or, broadly defined, stresses. Responding to stresses, cells either choose to restore or reprogram their gene expression patterns. This decision is partly mediated by miRNA functions, in particular by modulating the amount of miRNAs, the amount of mRNA targets, or the activity/mode of action of miRNA-protein complexes. In turn, these changes determine the specificity, timing, and concentration of gene products expressed upon stresses. Dysregulation of these processes contributes to chronic diseases, including cancers.

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Available from: Anthony K. L. Leung,
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    • "miRNA activity during stress and ageing can be also modulated by specific RNA-binding proteins that bind adjacent to miRNA binding sites and control the expression of the same target mRNA. Furthermore, stress can affect the expression or the processing of miRNAs through changes in related transcription factors or signaling molecules (Leung and Sharp, 2010). Although miRNA abundance is highly regulated at the biogenesis and processing levels, degradation mechanisms that control their half-lives are similarly important for miRNA homeostasis in all conditions. "
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    ABSTRACT: Messenger RNA (mRNA) turnover that determines the lifetime of cytoplasmic mRNAs is a means to control gene expression under both normal and stress conditions, whereas its impact on ageing and age-related disorders has just become evident. Gene expression control is achieved at the level of the mRNA clearance as well as mRNA stability and accessibility to other molecules. All these processes are regulated by cis-acting motifs and trans-acting factors that determine the rates of translation and degradation of transcripts. Specific messenger RNA granules that harbor the mRNA decay machinery or various factors, involved in translational repression and transient storage of mRNAs, are also part of the mRNA fate regulation. Their assembly and function can be modulated to promote stress resistance in adverse conditions and over time affect the ageing process and the lifespan of the organism. Here, we provide insights into the complex relationships of ageing modulators and mRNA turnover mechanisms.
    Mechanisms of ageing and development 10/2015; 152. DOI:10.1016/j.mad.2015.09.006 · 3.40 Impact Factor
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    • "disease or oxidative stress status) can be stably inherited for a number of generations (Cuzin, Grandjean & Rassoulzadegan 2008). Indeed, miRNAs are suggested to play a large role in regulating the response to both acute and chronic environmental stress, by programming the cell's gene expression during development to be able to acclimatize to the new environment in the long run (Leung & Sharp 2010). Thus, their role in the processes of acclimatization and adaptation to urban habitats represents an intriguing venue for future research. "
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    ABSTRACT: 1.To estimate the impact of urbanisation on wild animals, it is important to know how different species, populations and/or individuals deal with and respond to environmental stress. Are more urbanised species adapted to their environment; or do individuals acclimatize over the course of their life? Alternatively, do they simply cope at the expense of other functions? These are three key processes that I will address using two important physiological responses as case traits, namely oxidative stress and inflammation, - which are known to be under genetic control as well as showing great plasticity.2.Oxidative stress is a state of more reactive oxidants than antioxidants, which may cause tissue damage linked to disease and senescence. Inflammation, on the other hand, is the response of vascular tissues to harmful stimuli. However, under progressive stimuli inflammation may also cause tissue destruction and pathology.3.Although patterns and strengths of effects are not always clear cut, the often interconnected oxidative stress and inflammation have the potential to be severely affected by urban stressors, thereby mechanistically link ecology to fitness. Here I discuss five major urban stressors: chemical-, noise- and artificial night light pollution, disease and diet, and how their individual and combinatory effects may affect these two physiological responses.4.To start to disentangle whether physiological responses are a question of evolving, acclimatizing or coping with the urban environment, population genetics along with regulatory mechanisms of gene expression will shed light on the “costs” of urban life, and help to understand why some species or genotypes thrive, while others are absent, in urban areas. Single gene polymorphism (SNP) has been successful for explaining local adaptation and tolerance towards acute toxic substances. However, for multiple stressors acting in concert, at low chronic exposure, investigations of epigenetic mechanisms regulating gene expression may be more illuminating.5.Here I review the pathways by which genetic and epigenetic mechanisms can affect oxidative stress and inflammatory responses in urban environments, thereby affecting overall fitness. By doing so, I identify the major outstanding gaps of knowledge in the interfaces between ecology, toxicology, evolutionary and molecular biology to inform future studies of urban wildlife.This article is protected by copyright. All rights reserved.
    Functional Ecology 05/2015; 29(7). DOI:10.1111/1365-2435.12477 · 4.83 Impact Factor
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    • "Emerging studies suggest that stress can alter miRNA biogenesis (Leung and Sharp, 2010). Our study revealed a direct and tight control of Drosha by stress conditions and an unexpected critical role of this regulation in cell survival. "
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    ABSTRACT: MicroRNAs (miRNAs) regulate the translational potential of their mRNA targets and control many cellular processes. The key step in canonical miRNA biogenesis is the cleavage of the primary transcripts by the nuclear RNase III enzyme Drosha. Emerging evidence suggests that the miRNA biogenic cascade is tightly controlled. However, little is known whether Drosha is regulated. Here, we show that Drosha is targeted by stress. Under stress, p38 MAPK directly phosphorylates Drosha at its N terminus. This reduces its interaction with DiGeorge syndrome critical region gene 8 and promotes its nuclear export and degradation by calpain. This regulatory mechanism mediates stress-induced inhibition of Drosha function. Reduction of Drosha sensitizes cells to stress and increases death. In contrast, increase in Drosha attenuates stress-induced death. These findings reveal a critical regulatory mechanism by which stress engages p38 MAPK pathway to destabilize Drosha and inhibit Drosha-mediated cellular survival. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular Cell 02/2015; 57(4):721-734. DOI:10.1016/j.molcel.2015.01.004 · 14.02 Impact Factor
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