Binding of nerve growth factor to its p75 receptor in stressed cells induces selective IkappaB-beta degradation and NF-kappaB nuclear translocation.
Nerve growth factor (NGF) regulates the activity of the transcription factor NF-kappaB (nuclear factor-kappaB) through its low affinity receptor, p75. In the present study we found that NGF binding to p75 induces nuclear translocation of p65 and increases NF-kappaB binding activity in a cell line overexpressing p75, but only after the cells have been subjected to a previous stress. Under physiological conditions, in the absence of stress, NGF is unable to alter p65 nuclear levels. Tumor necrosis factor-alpha (TNF-alpha) induces a down-regulation of IkappaB-alpha, -beta and -epsilon both in physiological and in stress, i.e. serum-free, conditions. In contrast, NGF only induces the specific degradation of IkappaB-beta after serum withdrawal, without affecting IkappaB-alpha or -epsilon either in the presence or in the absence of stress. IkappaB-beta consists of several isoforms, whose relative abundance is regulated by serum withdrawal. NGF does not target all the IkappaB-beta isoforms with the same potency, being more effective in reducing the levels of the isoforms up-regulated by serum withdrawal. TRAF-6 is expressed at the same level under both physiological and stress conditions. These results indicate that NGF is able to induce NF-kappaB nuclear translocation by a mechanism that involves specific IkappaB-beta degradation only after the cells have been subjected to a severe stress.
Cosgaya
J M
JM
Department of Neurobiology, Stanford University School of Medicine, Stanford, California 93305, USA.
Shooter
E M
EM
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001790:Blood Physiological Phenomena; D002460:Cell Line; D020672:I-kappa B Proteins / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism* / Q000473:pathology; D048029:TNF Receptor-Associated Factor 6
D020672:I-kappa B Proteins; D016328:NF-kappa B; D020033:Protein Isoforms; D011506:Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D048029:TNF Receptor-Associated Factor 6; D020932:Nerve Growth Factor