title: NRP/B mutations impair Nrf2-dependent NQO1 induction in human primary brain tumors.
abstract: Brain tumors are associated with genetic alterations of oncogenes and tumor suppressor genes. Accumulation of reactive oxygen species (ROS) in cells leads to oxidative stress-induced damage, resulting in tumorigenesis. Here, we showed that the nuclear matrix protein nuclear restricted protein in brain (NRP/B) was colocalized and interacted with NF-E2-related factor 2 (Nrf2). During oxidative stress response, NRP/B expression and its interaction with Nrf2 were upregulated in SH-SY5Y cells. Association of NRP/B with Nrf2 was crucial for NAD(P)H:quinone oxidoreductase 1 (NQO1) expression. NRP/B was localized predominantly in the nucleus of normal brain cells, whereas in primary brain tumors NRP/B was almost exclusively contained in the cytoplasm. In addition, unlike wild-type NRP/B, the expression of NRP/B mutants isolated from primary brain tumors was found in the cytoplasm, and these mutants failed to induce Nrf2-dependent NQO1 transcription. Thus, NRP/B mutations and their altered localization resulted in changes in NRP/B function and deregulation of Nrf2-dependent NQO1 activation in brain tumors. This study provides insights into the mechanism by which the NRP/B modulates Nrf2-dependent NQO1 induction in cellular protection against ROS in brain tumors.
authors.affiliation: Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: S
authors.initials: S
authors.lastname: Seng
authors.forename: H K
authors.initials: HK
authors.lastname: Avraham
authors.forename: G
authors.initials: G
authors.lastname: Birrane
authors.forename: S
authors.initials: S
authors.lastname: Jiang
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: G
authors.initials: G
authors.lastname: Katz
authors.forename: C E
authors.initials: CE
authors.lastname: Bass
authors.forename: R
authors.initials: R
authors.lastname: Zagozdzon
authors.forename: S
authors.initials: S
authors.lastname: Avraham
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021381:Protein Transport
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D008840:Microfilament Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009479:Neuropeptides; D009687:Nuclear Proteins; D016877:Oxidants; D010750:Phosphoproteins; C112302:ectodermal-neural cortex 1 protein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human