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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology
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Cell Nucleus / metabolism
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Cytoplasm / metabolism
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Enzyme Activation
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Green Fluorescent Proteins / metabolism
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Humans
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Hydrogen Peroxide / pharmacology
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Immunoprecipitation
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Intracellular Signaling Peptides and Proteins / metabolism
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Kelch-Like ECH-Associated Protein 1
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Mice
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Microfilament Proteins / genetics*
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Microfilament Proteins / immunology
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Microfilament Proteins / metabolism
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Mutation / genetics*
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NAD(P)H Dehydrogenase (Quinone) / genetics
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NAD(P)H Dehydrogenase (Quinone) / metabolism*
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NF-E2-Related Factor 2 / metabolism*
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Neuropeptides / genetics*
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Neuropeptides / immunology
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Neuropeptides / metabolism
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Nuclear Proteins / genetics*
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Nuclear Proteins / immunology
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Nuclear Proteins / metabolism
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Oxidants / pharmacology
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Oxidative Stress
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Phosphoproteins / metabolism
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Promoter Regions, Genetic
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Protein Transport
Substances
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Intracellular Signaling Peptides and Proteins
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KEAP1 protein, human
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Kelch-Like ECH-Associated Protein 1
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Microfilament Proteins
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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Neuropeptides
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Nuclear Proteins
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Oxidants
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Phosphoproteins
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ectodermal-neural cortex 1 protein
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Hydrogen Peroxide
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NAD(P)H Dehydrogenase (Quinone)
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NQO1 protein, human