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A latent pro-survival function for the Mir-290-295 cluster in mouse embryonic stem cells
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نویسنده
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zheng g.x.y. ,ravi a. ,calabrese j.m. ,medeiros l.a. ,kirak o. ,dennis l.m. ,jaenisch r. ,burge c.b. ,sharp p.a.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 5
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چکیده
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Micrornas (mirnas) post-transcriptionally regulate the expression of thousands of distinct mrnas. while some regulatory interactions help to maintain basal cellular functions,others are likely relevant in more specific settings,such as response to stress. here we describe such a role for the mir-290-295 cluster,the dominant mirna cluster in mouse embryonic stem cells (mescs). examination of a target list generated from bioinformatic prediction,as well as expression data following mirna loss,revealed strong enrichment for apoptotic regulators,two of which we validated directly: caspase 2,the most highly conserved mammalian caspase,and ei24,a p53 transcriptional target. consistent with these predictions,mescs lacking mirnas were more likely to initiate apoptosis following genotoxic exposure to gamma irradiation or doxorubicin. knockdown of either candidate partially rescued this pro-apoptotic phenotype,as did transfection of members of the mir-290-295 cluster. these findings were recapitulated in a specific mir-290-295 deletion line,confirming that they reflect mirna functions at physiological levels. in contrast to the basal regulatory roles previously identified,the pro-survival phenotype shown here may be most relevant to stressful gestations,where pro-oxidant metabolic states induce dna damage. similarly,this cluster may mediate chemotherapeutic resistance in a neoplastic context,making it a useful clinical target. © 2011 zheng et al.
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آدرس
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mit koch institute for integrative cancer research,cambridge,ma,united states,computational and systems biology graduate program,massachusetts institute of technology,cambridge,ma,united states,department of biology,massachusetts institute of technology,cambridge,ma,united states,howard hughes medical institute,program in epithelial biology,stanford school of medicine,stanford,ca, United States, mit koch institute for integrative cancer research,cambridge,ma,united states,department of biology,massachusetts institute of technology,cambridge,ma,united states,harvard-mit health sciences and technology program,cambridge,ma, United States, mit koch institute for integrative cancer research,cambridge,ma,united states,department of biology,massachusetts institute of technology,cambridge,ma,united states,department of genetics,carolina center for genome sciences,university of north carolina,chapel hill,nc, United States, department of biology,massachusetts institute of technology,cambridge,ma,united states,whitehead institute for biomedical research,cambridge,ma, United States, whitehead institute for biomedical research,cambridge,ma, United States, department of biology,massachusetts institute of technology,cambridge,ma,united states,whitehead institute for biomedical research,cambridge,ma,united states,nanostring technologies,seattle,wa, United States, department of biology,massachusetts institute of technology,cambridge,ma,united states,whitehead institute for biomedical research,cambridge,ma, United States, computational and systems biology graduate program,massachusetts institute of technology,cambridge,ma,united states,department of biology,massachusetts institute of technology,cambridge,ma, United States, mit koch institute for integrative cancer research,cambridge,ma,united states,department of biology,massachusetts institute of technology,cambridge,ma, United States
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Authors
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