p75-nerve growth factor as an antiapoptotic complex: independence versus cooperativity in protection from enediyne chemotherapeutic agents

Growth factors, including nerve growth factor (NGF), have been hypothesized to play a role in resistance to chemotherapeutic agent-induced apoptosis. Induction by NGF of resistance to apoptosis is primarily thought to be the result of its binding to its high-affinity receptor, TrkA. The low-affinity...

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Bibliographic Details
Published in:	Molecular pharmacology Vol. 61; no. 4; p. 710
Main Authors:	Yan, Chaohua, Liang, Ye, Nylander, Karen D, Wong, Judith, Rudavsky, Rena M, Saragovi, H Uri, Schor, Nina Felice
Format:	Journal Article
Language:	English
Published:	United States 01-04-2002
Subjects:	Antibiotics, Antineoplastic - pharmacology Antibodies, Monoclonal - pharmacology Apoptosis - physiology Binding Sites Nerve Growth Factors - immunology Nerve Growth Factors - physiology NF-kappa B - metabolism Protective Agents - pharmacology Receptor, Nerve Growth Factor - metabolism Receptor, Nerve Growth Factor - physiology Receptor, trkA - metabolism Receptor, trkA - physiology Signal Transduction - physiology Tumor Cells, Cultured Zinostatin - pharmacology
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Summary:	Growth factors, including nerve growth factor (NGF), have been hypothesized to play a role in resistance to chemotherapeutic agent-induced apoptosis. Induction by NGF of resistance to apoptosis is primarily thought to be the result of its binding to its high-affinity receptor, TrkA. The low-affinity NGF receptor, p75, has long been thought merely to facilitate NGF binding to TrkA. However, we have previously shown that the binding of NGF to its low-affinity receptor, p75, protects neuroblastoma cells that do not express TrkA against apoptosis induced by enediyne chemotherapeutic agents. In cells that express both receptors, it is not clear what determines which receptor is responsible for the protective effect of NGF. We now show that, in enediyne-treated SH-SY5Y neuroblastoma transfectants with native levels of p75 and a low TrkA/p75 ratio (1/100), the anti-apoptotic effect of NGF requires binding to p75. In contrast, in transfectants with native levels of p75 and a high TrkA/p75 ratio (100/100), NGF treatment prevents enediyne-induced apoptosis by a mechanism independent of p75 binding. Treatment of low TrkA/p75 ratio cells with NGF results in activation and nuclear translocation of NF-kappaB and tyrosine phosphorylation of TrkA. Analogous treatment of high TrkA/p75 ratio cells results only in phosphorylation of TrkA even though nuclear factor (NF)-kappaB signaling is not inactive and can be initiated by other ligands. The ratio of TrkA/p75 in cells that express both receptors probably contributes to the determination of which of the two known roles of p75 (i.e., TrkA independent or TrkA facilitatory) are responsible for NGF-mediated protection from enediyne-induced apoptosis.
ISSN:	0026-895X
DOI:	10.1124/mol.61.4.710