p75NTR is highly expressed in vestibular schwannomas and promotes cell survival by activating nuclear transcription factor κB

Iram Ahmad; Wei Ying Yue; Augusta Fernando; J Jason Clark; Erika A Woodson; Marlan R Hansen

doi:10.1002/glia.22709

Back

p75NTR is highly expressed in vestibular schwannomas and promotes cell survival by activating nuclear transcription factor κB

Journal article

Peer reviewed

p75NTR is highly expressed in vestibular schwannomas and promotes cell survival by activating nuclear transcription factor κB

Iram Ahmad, Wei Ying Yue, Augusta Fernando, J Jason Clark, Erika A Woodson and Marlan R Hansen

Glia, Vol.62(10), pp.1699-1712

10/2014

DOI: 10.1002/glia.22709

PMCID: PMC4150679

PMID: 24976126

Files and links (1)

url

http://doi.org/10.1002/glia.22709View

Open Access

Abstract

Vestibular schwannomas (VSs) arise from Schwann cells (SCs) and result from the loss of function of merlin, the protein product of the NF2 tumor suppressor gene. In contrast to non-neoplastic SCs, VS cells survive long-term in the absence of axons. We find that p75(NTR) is overexpressed in VSs compared with normal nerves, both at the transcript and protein level, similar to the response of non-neoplastic SCs following axotomy. Despite elevated p75(NTR) expression, VS cells are resistant to apoptosis due to treatment with proNGF, a high affinity ligand for p75(NTR) . Furthermore, treatment with proNGF protects VS cells from apoptosis due to c-Jun N-terminal kinase (JNK) inhibition indicating that p75(NTR) promotes VS cell survival. Treatment of VS cells with proNGF activated NF-κB while inhibition of JNK with SP600125 or siRNA-mediated knockdown reduced NF-κB activity. Significantly, proNGF also activated NF-κB in cultures treated with JNK inhibitors. Thus, JNK activity appears to be required for basal levels of NF-κB activity but not for proNGF-induced NF-κB activity. To confirm that the increase in NF-κB activity contributes to the prosurvival effect of proNGF, we infected VS cultures with Ad.IκB.SerS32/36A virus, which inhibits NF-κB activation. Compared with control virus, Ad.IκB.SerS32/36A significantly increased apoptosis including in VS cells treated with proNGF. Thus, in contrast to non-neoplastic SCs, p75(NTR) signaling provides a prosurvival response in VS cells by activating NF-κB independent of JNK. Such differences may contribute to the ability of VS cells to survive long-term in the absence of axons.

Sciatic Nerve - physiology

NF-kappa B - antagonists & inhibitors

JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors

Nerve Growth Factor - metabolism

Humans

Cells, Cultured

Rats

JNK Mitogen-Activated Protein Kinases - metabolism

NF-kappa B - metabolism

Receptors, Nerve Growth Factor - metabolism

Neuroma, Acoustic - physiopathology

Protein Precursors - metabolism

Nerve Tissue Proteins - metabolism

Animals

Schwann Cells - physiology

Mice

Apoptosis - physiology

Cell Survival - physiology

NF-kappa B - agonists

Details

Title: Subtitle: p75NTR is highly expressed in vestibular schwannomas and promotes cell survival by activating nuclear transcription factor κB
Creators: Iram Ahmad - Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa
Wei Ying Yue
Augusta Fernando
J Jason Clark
Erika A Woodson
Marlan R Hansen
Resource Type: Journal article
Publication Details: Glia, Vol.62(10), pp.1699-1712
DOI: 10.1002/glia.22709
PMID: 24976126
PMCID: PMC4150679
NLM abbreviation: Glia
ISSN: 0894-1491
eISSN: 1098-1136
Publisher: United States
Grant note: R01DC009801 / NIDCD NIH HHS T32 DC000040 / NIDCD NIH HHS R01 DC009801 / NIDCD NIH HHS T32DC00040 / NIDCD NIH HHS P30DC010362 / NIDCD NIH HHS P30 DC010362 / NIDCD NIH HHS
Language: English
Date published: 10/2014
Academic Unit: Molecular Physiology and Biophysics; Neurosurgery; Otolaryngology
Record Identifier: 9984007293702771

Metrics

14 Record Views

27 Times Cited - Web of Science