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MicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20).

Constitutive activation of the NF-[kappa]B pathway is associated with diffuse large B-cell lymphoma (DLBCL) pathogenesis, but whether microRNA dysfunction can contribute to these events remains unclear. Starting from an integrative screening strategy, we uncovered that the negative NF-[kappa]B regul... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America May 15, 2012, Vol.109(20), pp.7865-7870
Main Author: Kim, Sang-Woo
Other Authors: Ramasamy, Kumaraguruparan , Bouamar, Hakim , Lin, An-Ping , Jiang, Daifeng , Aguiar, Ricardo C T
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1200081109
Link: http://search.proquest.com/docview/1014113934/?pq-origsite=primo
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title: MicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20).
format: Article
creator:
  • Kim, Sang-Woo
  • Ramasamy, Kumaraguruparan
  • Bouamar, Hakim
  • Lin, An-Ping
  • Jiang, Daifeng
  • Aguiar, Ricardo C T
subjects:
  • Cell Line–Metabolism
  • DNA-Binding Proteins–Metabolism
  • Gene Expression Profiling–Metabolism
  • Humans–Metabolism
  • Immunoblotting–Metabolism
  • Immunoprecipitation–Physiology
  • Intracellular Signaling Peptides and Proteins–Physiology
  • Micrornas–Physiology
  • Nf-Kappa B–Physiology
  • Nuclear Proteins–Physiology
  • Real-Time Polymerase Chain Reaction–Physiology
  • Signal Transduction–Physiology
  • Statistics, Nonparametric–Physiology
  • Subcellular Fractions–Physiology
  • Tumor Necrosis Factor Alpha-Induced Protein 3–Physiology
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mirn125 Microrna, Human
  • Micrornas
  • Nf-Kappa B
  • Nuclear Proteins
  • Tnfaip3 Protein, Human
  • Tumor Necrosis Factor Alpha-Induced Protein 3
ispartof: Proceedings of the National Academy of Sciences of the United States of America, May 15, 2012, Vol.109(20), pp.7865-7870
description: Constitutive activation of the NF-[kappa]B pathway is associated with diffuse large B-cell lymphoma (DLBCL) pathogenesis, but whether microRNA dysfunction can contribute to these events remains unclear. Starting from an integrative screening strategy, we uncovered that the negative NF-[kappa]B regulator TNFAIP3 is a direct target of miR-125a and miR-125b, which are commonly gained and/or overexpressed in DLBCL. Ectopic expression of these microRNAs in multiple cell models enhanced K63-linked ubiquitination of proximal signaling complexes and elevated NF-[kappa]B activity, leading to aberrant expression of its transcriptional targets and the development of a proproliferative and antiapoptotic phenotype in malignant B cells. Concordantly, genetic inhibition of miR-125a/miR-125b blunted NF-[kappa]B signals, whereas rescue assays and genetic modulation of a TNFAIP3-null model defined the essential role of the TNFAIP3 targeting on miR-125a/ miR-125b-mediated lymphomagenesis. Importantly, miR-125a/mir-125b effects on TNFAIP3 expression and NF-[kappa]B activity were confirmed in a well-characterized cohort of primary DLBCLs. Our data delineate a unique epigenetic model for aberrant activation of the NF-[kappa]B pathway in cancer and provide a coherent mechanism for the role of these miRNAs in immune cell activation and hematopoiesis. Further, as miR-125b is a direct NF-[kappa]B transcriptional target, our results suggest the presence of a positive self-regulatory loop whereby termination of TNFAIP3 function by miR-125 could strengthen and prolong NF-[kappa]B activity. doi/10.1073/pnas.1200081109
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1200081109
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleMicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20).
creatorKim, Sang-Woo ; Ramasamy, Kumaraguruparan ; Bouamar, Hakim ; Lin, An-Ping ; Jiang, Daifeng ; Aguiar, Ricardo C T
contributorKim, Sang-Woo (correspondence author) ; Kim, Sang-Woo (record owner)
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identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1200081109
subjectCell Line–Metabolism ; DNA-Binding Proteins–Metabolism ; Gene Expression Profiling–Metabolism ; Humans–Metabolism ; Immunoblotting–Metabolism ; Immunoprecipitation–Physiology ; Intracellular Signaling Peptides and Proteins–Physiology ; Micrornas–Physiology ; Nf-Kappa B–Physiology ; Nuclear Proteins–Physiology ; Real-Time Polymerase Chain Reaction–Physiology ; Signal Transduction–Physiology ; Statistics, Nonparametric–Physiology ; Subcellular Fractions–Physiology ; Tumor Necrosis Factor Alpha-Induced Protein 3–Physiology ; DNA-Binding Proteins ; Intracellular Signaling Peptides and Proteins ; Mirn125 Microrna, Human ; Micrornas ; Nf-Kappa B ; Nuclear Proteins ; Tnfaip3 Protein, Human ; Tumor Necrosis Factor Alpha-Induced Protein 3
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descriptionConstitutive activation of the NF-[kappa]B pathway is associated with diffuse large B-cell lymphoma (DLBCL) pathogenesis, but whether microRNA dysfunction can contribute to these events remains unclear. Starting from an integrative screening strategy, we uncovered that the negative NF-[kappa]B regulator TNFAIP3 is a direct target of miR-125a and miR-125b, which are commonly gained and/or overexpressed in DLBCL. Ectopic expression of these microRNAs in multiple cell models enhanced K63-linked ubiquitination of proximal signaling complexes and elevated NF-[kappa]B activity, leading to aberrant expression of its transcriptional targets and the development of a proproliferative and antiapoptotic phenotype in malignant B cells. Concordantly, genetic inhibition of miR-125a/miR-125b blunted NF-[kappa]B signals, whereas rescue assays and genetic modulation of a TNFAIP3-null model defined the essential role of the TNFAIP3 targeting on miR-125a/ miR-125b-mediated lymphomagenesis. Importantly, miR-125a/mir-125b effects on TNFAIP3 expression and NF-[kappa]B activity were confirmed in a well-characterized cohort of primary DLBCLs. Our data delineate a unique epigenetic model for aberrant activation of the NF-[kappa]B pathway in cancer and provide a coherent mechanism for the role of these miRNAs in immune cell activation and hematopoiesis. Further, as miR-125b is a direct NF-[kappa]B transcriptional target, our results suggest the presence of a positive self-regulatory loop whereby termination of TNFAIP3 function by miR-125 could strengthen and prolong NF-[kappa]B activity. doi/10.1073/pnas.1200081109
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