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IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65

The diffusely infiltrative nature of glioblastoma (GBM) makes them highly recurrent. IGF2 mRNA-binding protein 3 (IMP3), a GBM upregulated RNA binding protein, promotes glioma cell migration. An integrative bioinformatics analysis identified p65 (RELA), a subunit of NF-κB heterodimer as a target and...

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Autores principales: Bhargava, Shruti, Visvanathan, Abhirami, Patil, Vikas, Kumar, Anuj, Kesari, Santosh, Das, Saumitra, Hegde, Alangar S, Arivazhagan, Arimappamagan, Santosh, Vani, Somasundaram, Kumaravel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522290/
https://www.ncbi.nlm.nih.gov/pubmed/28465487
http://dx.doi.org/10.18632/oncotarget.17118
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author Bhargava, Shruti
Visvanathan, Abhirami
Patil, Vikas
Kumar, Anuj
Kesari, Santosh
Das, Saumitra
Hegde, Alangar S
Arivazhagan, Arimappamagan
Santosh, Vani
Somasundaram, Kumaravel
author_facet Bhargava, Shruti
Visvanathan, Abhirami
Patil, Vikas
Kumar, Anuj
Kesari, Santosh
Das, Saumitra
Hegde, Alangar S
Arivazhagan, Arimappamagan
Santosh, Vani
Somasundaram, Kumaravel
author_sort Bhargava, Shruti
collection PubMed
description The diffusely infiltrative nature of glioblastoma (GBM) makes them highly recurrent. IGF2 mRNA-binding protein 3 (IMP3), a GBM upregulated RNA binding protein, promotes glioma cell migration. An integrative bioinformatics analysis identified p65 (RELA), a subunit of NF-κB heterodimer as a target and an important mediator of IMP3 promoted glioma cell migration. IMP3 increased p65 protein levels without any change in p65 transcript levels, but promoted its polysome association. RIP-PCR demonstrated the binding of IMP3 to p65 transcript. UV crosslinking experiments with in vitro transcribed RNA confirmed the specific and direct binding of IMP3 to sites on p65 3′UTR. Further, IMP3 induced luciferase activity from p65 3′UTR reporter carrying wild type sites but not mutated sites. Exogenous overexpression of p65 from a 3′UTR-less construct rescued the reduced migration of glioma cells in IMP3 silenced condition. In addition, IMP3 silencing inhibited glioma stem-like cell maintenance and migration. The exogenous overexpression of 3′UTR-less p65 significantly alleviated the inhibition of neurosphere formation observed in IMP3 silenced glioma stem-like cells. Further, we show that IMP3 is transcriptionally activated by NF-κB pathway indicating the presence of a positive feedback loop between IMP3 and p65. This study establishes p65 as a novel target of IMP3 in increasing glioma cell migration and underscores the significance of IMP3-p65 feedback loop for therapeutic targeting in GBM.
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spelling pubmed-55222902017-08-21 IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65 Bhargava, Shruti Visvanathan, Abhirami Patil, Vikas Kumar, Anuj Kesari, Santosh Das, Saumitra Hegde, Alangar S Arivazhagan, Arimappamagan Santosh, Vani Somasundaram, Kumaravel Oncotarget Research Paper The diffusely infiltrative nature of glioblastoma (GBM) makes them highly recurrent. IGF2 mRNA-binding protein 3 (IMP3), a GBM upregulated RNA binding protein, promotes glioma cell migration. An integrative bioinformatics analysis identified p65 (RELA), a subunit of NF-κB heterodimer as a target and an important mediator of IMP3 promoted glioma cell migration. IMP3 increased p65 protein levels without any change in p65 transcript levels, but promoted its polysome association. RIP-PCR demonstrated the binding of IMP3 to p65 transcript. UV crosslinking experiments with in vitro transcribed RNA confirmed the specific and direct binding of IMP3 to sites on p65 3′UTR. Further, IMP3 induced luciferase activity from p65 3′UTR reporter carrying wild type sites but not mutated sites. Exogenous overexpression of p65 from a 3′UTR-less construct rescued the reduced migration of glioma cells in IMP3 silenced condition. In addition, IMP3 silencing inhibited glioma stem-like cell maintenance and migration. The exogenous overexpression of 3′UTR-less p65 significantly alleviated the inhibition of neurosphere formation observed in IMP3 silenced glioma stem-like cells. Further, we show that IMP3 is transcriptionally activated by NF-κB pathway indicating the presence of a positive feedback loop between IMP3 and p65. This study establishes p65 as a novel target of IMP3 in increasing glioma cell migration and underscores the significance of IMP3-p65 feedback loop for therapeutic targeting in GBM. Impact Journals LLC 2017-04-15 /pmc/articles/PMC5522290/ /pubmed/28465487 http://dx.doi.org/10.18632/oncotarget.17118 Text en Copyright: © 2017 Bhargava et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Bhargava, Shruti
Visvanathan, Abhirami
Patil, Vikas
Kumar, Anuj
Kesari, Santosh
Das, Saumitra
Hegde, Alangar S
Arivazhagan, Arimappamagan
Santosh, Vani
Somasundaram, Kumaravel
IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65
title IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65
title_full IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65
title_fullStr IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65
title_full_unstemmed IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65
title_short IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65
title_sort igf2 mrna binding protein 3 (imp3) promotes glioma cell migration by enhancing the translation of rela/p65
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522290/
https://www.ncbi.nlm.nih.gov/pubmed/28465487
http://dx.doi.org/10.18632/oncotarget.17118
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