NRP/B mutations impair Nrf2-dependent NQO1 induction in human primary brain tumors.
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.
Seng
S
S
Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Avraham
H K
HK
Birrane
G
G
Jiang
S
S
Li
H
H
Katz
G
G
Bass
C E
CE
Zagozdzon
R
R
Avraham
S
S
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
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