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Plos Biology : the Hilda Complex Coordinates a Conditional Switch in the 39-untranslated Region of the Vegfa Mrna, Volume 11

By Anderson, Paul

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Book Id: WPLBN0003922731
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Biology : the Hilda Complex Coordinates a Conditional Switch in the 39-untranslated Region of the Vegfa Mrna, Volume 11  
Author: Anderson, Paul
Volume: Volume 11
Language: English
Subject: Journals, Science, Biology
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Biology
Historic
Publication Date:
Publisher: Plos

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Anderson, P. (n.d.). Plos Biology : the Hilda Complex Coordinates a Conditional Switch in the 39-untranslated Region of the Vegfa Mrna, Volume 11. Retrieved from http://netlibrary.net/


Description
Description : Cell regulatory circuits integrate diverse, and sometimes conflicting, environmental cues to generate appropriate, conditiondependent responses. Here, we elucidate the components and mechanisms driving a protein-directed RNA switch in the 39UTR of vascular endothelial growth factor (VEGF)-A. We describe a novel HILDA (hypoxia-inducible hnRNP L–DRBP76– hnRNP A2/B1) complex that coordinates a three-element RNA switch, enabling VEGFA mRNA translation during combined hypoxia and inflammation. In addition to binding the CA-rich element (CARE), heterogeneous nuclear ribonucleoprotein (hnRNP) L regulates switch assembly and function. hnRNP L undergoes two previously unrecognized, condition-dependent posttranslational modifications : IFN-c induces prolyl hydroxylation and von Hippel-Lindau (VHL)-mediated proteasomal degradation, whereas hypoxia stimulates hnRNP L phosphorylation at Tyr359, inducing binding to hnRNP A2/B1, which stabilizes the protein. Also, phospho-hnRNP L recruits DRBP76 (double-stranded RNA binding protein 76) to the 39UTR, where it binds an adjacent AU-rich stem-loop (AUSL) element, ‘‘flipping’’ the RNA switch by disrupting the GAIT (interferongamma- activated inhibitor of translation) element, preventing GAIT complex binding, and driving robust VEGFA mRNA translation. The signal-dependent, HILDA complex coordinates the function of a trio of neighboring RNA elements, thereby regulating translation of VEGFA and potentially other mRNA targets. The VEGFA RNA switch might function to ensure appropriate angiogenesis and tissue oxygenation during conflicting signals from combined inflammation and hypoxia. We propose the VEGFA RNA switch as an archetype for signal-activated, protein-directed, multi-element RNA switches that regulate posttranscriptional gene expression in complex environments.

 

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