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RETRACTED ARTICLE: Genetic alterations of the NRP/B gene are associated with human brain tumors

Oncogene volume 23, pages 5890–5900 (2004)Cite this article

This article was retracted on 02 June 2023

This article has been updated

Abstract

Nearly all brain tumors develop following the progressive accumulation of genetic alterations of oncogenes and tumor suppressor genes (such as p53 and retinoblastoma protein). Furthermore, aberrations in the nuclear matrix often contribute to genomic instabilities and the development of cancer. We have previously shown that nuclear-restricted protein/brain (NRP/B), a member of the BTB/Kelch repeat family, is a nuclear matrix protein normally expressed in neurons but not in astrocytes, and that it is an early and specific marker of neurons during the development of the central nervous system. Here, we show aberrant expression of NRP/B in human brain tissues. NRP/B is expressed in the cytoplasm of human brain tumor cells (glioblastoma, GBM) arising from astrocytes. NRP/B mutations (13 mutations in the Kelch domains, two in the intervening sequence (IVS) domain and two in the BTB domain) were detected in brain tumor cell lines (A-172, CCF-STTG1, SK-N-SH and U87-MG) and in primary human malignant GBM tissues (eight samples). More importantly, we found that NRP/B mutants, but not wild-type (wt) NRP/B, increased the activation of ERK and consequently promoted cell proliferation, attenuated caspase activation and suppressed the cellular apoptosis induced by the stressful stimulus cisplatin (10 μ M). These events were observed to occur via a p53-mediated pathway. In addition, while wt NRP/B was associated with actin, mutations in the Kelch domains of NRP/B led to its reduced binding affinity to actin. Thus, alterations and gene mutations within the NRP/B gene may contribute to brain tumorigenesis by promoting cell proliferation, suppressing apoptosis and by affecting nuclear cytoskeleton dynamics.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Change history

Abbreviations

BrdU:

5-bromodeoxyuridine

CNS:

central nervous system

DAPI:

4′-6 diamidino-2-phenylindole

ENC-1:

ectodermal-neural cortex

GBMs:

glioblastomas

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

IVS:

intervening sequence

mt:

mutant

O2A:

oligodendroglial type 2 astrocyte

NRP/B:

nuclear-restricted protein/brain

PIG 10:

p53-induced protein 10

RT–PCR:

reverse transcription–PCR

wt:

wild type

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Acknowledgements

We thank Drs G Pledis (Beth Israel Deaconess Medical Center) for providing human GBM samples and B Vogelstein for providing the HCT 116 p53+/+ and p53−/− cells. We thank Dr Jerome E Groopman for his support, Dr Tae Kim for technical advice, Janet Delahanty for editing the manuscript, and Heather Kil for typing assistance. This paper is dedicated to Charlene Engelhard, the Recanati family, and Ronald Ansin for their continuing friendship and support for our research program. This work was supported in part by the National Institutes of Health Grants 1R01 CA096805 (HA), K18 Career Enhancement Award (PAR-02-069) (HA), the Susan G Komen Breast Cancer Foundation Award (SA), the Department of Army concept Award (SA), and 1R01 NS046628-01A1 (SA).

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  1. Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, 02115, MA, USA

    Xing-Qun Liang, Hava Karsenty Avraham, Shuxian Jiang & Shalom Avraham

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Correspondence to Shalom Avraham.

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Liang, XQ., Avraham, H., Jiang, S. et al. RETRACTED ARTICLE: Genetic alterations of the NRP/B gene are associated with human brain tumors. Oncogene 23, 5890–5900 (2004). https://doi.org/10.1038/sj.onc.1207776

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