title: p75NTR is highly expressed in vestibular schwannomas and promotes cell survival by activating nuclear transcription factor κB.
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.
authors: Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa.
authors: Iram
authors: I
authors: Ahmad
authors: Wei Ying
authors: WY
authors: Yue
authors: Augusta
authors: A
authors: Fernando
authors: J Jason
authors: JJ
authors: Clark
authors: Erika A
authors: EA
authors: Woodson
authors: Marlan R
authors: MR
authors: Hansen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009464:Neuroma, Acoustic / Q000503:physiopathology*; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D012583:Schwann Cells / Q000502:physiology; D012584:Sciatic Nerve / Q000502:physiology
chemical_list: D016328:NF-kappa B; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C061397:pro-nerve growth factor, human; C068313:Ngfr protein, rat; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Schwann cell; acoustic neuroma; apoptosis; merlin; neurotrophin