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NRP/B mutations impair Nrf2-dependent NQO1 induction in human primary brain tumors

Oncogene volume 28, pages 378–389 (2009)Cite this article

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.

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Abbreviations

ARE:

antioxidant response element

GST:

glutathione S-transferase

H2O2:

hydrogen oxygenase

Keap1:

Kelch-like ECH-associated protein

Nrf2:

NF-E2-related factor 2

NRP/B:

nuclear restricted protein in brain

NQO1:

NAD(P)H:quinine oxidoreductase 1 (nicotinamide quinine oxidoreductase)

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Acknowledgements

We thank Janet Delahanty and Makara Men for editing the paper. This study was supported by NIH grants HL80699 (SA), CA096805 (HKA) and the Department of Defense Cancer Concept Award (SA).

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  1. Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    S Seng, H K Avraham, G Birrane, S Jiang, H Li, G Katz, C E Bass, R Zagozdzon & S Avraham

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  1. S Seng
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Correspondence to S Avraham.

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Seng, S., Avraham, H., Birrane, G. et al. NRP/B mutations impair Nrf2-dependent NQO1 induction in human primary brain tumors. Oncogene 28, 378–389 (2009). https://doi.org/10.1038/onc.2008.396

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