title: Partial rescue of geldanamycin-induced TrkA depletion by a proteasome inhibitor in PC12 cells.
abstract: In this work we tried to identify mechanisms that could explain how chemical inhibition of heat-shock protein 90 reduces nerve growth factor signaling in rat pheochromocytoma PC12 cells. Geldanamycin is an antibiotic originally discovered based on its ability to bind heat-shock protein 90. This interaction can lead to the disruption of heat-shock protein 90-containing multimolecular complexes. It can also induce the inhibition or even degradation of partner proteins dissociated from the 90 kDa chaperone and, eventually, can cause apoptosis, for instance, in PC12 cells. Before the onset of initial apoptotic events, however, a marked decrease in the activity of extracellular signal-regulated kinases ERK 1/2 and protein kinase B/Akt can be observed together with reduced expression of the high affinity nerve growth factor receptor, tropomyosine-related kinase, TrkA, in this cell type. The proteasome inhibitor MG-132 can effectively counteract the geldanamycin-induced reduction of TrkA expression and it can render TrkA and ERK1/2 phosphorylation but not that of protein kinase B/Akt by nerve growth factor again inducible. We have found altered intracellular distribution of TrkA in geldanamycin-treated and proteasome-inhibited PC12 cells that may, at least from the viewpoint of protein localization explain why nerve growth factor remains without effect on protein kinase B/Akt. The lack of protein kinase B/Akt stimulation by nerve growth factor in turn reveals why nerve growth factor treatment cannot save PC12 cells from geldanamycin-induced programmed cell death. Our observations can help to better understand the mechanism of action of geldanamycin, a compound with strong human therapeutical potential.
authors.affiliation: Department of Medical Biology, Medical School, University of Pécs, Pécs, Hungary H-7643, Pécs, Szigeti út 12., Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Berta
authors.forename: Alexandra
authors.initials: A
authors.lastname: Harci
authors.forename: Oktávia
authors.initials: O
authors.lastname: Tarjányi
authors.forename: Mónika
authors.initials: M
authors.lastname: Vecsernyés
authors.forename: András
authors.initials: A
authors.lastname: Balogh
authors.forename: Marianna
authors.initials: M
authors.lastname: Pap
authors.forename: József
authors.initials: J
authors.lastname: Szeberényi
authors.forename: György
authors.initials: G
authors.lastname: Sétáló
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D018613:Microscopy, Confocal; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D061988:Proteasome Inhibitors / Q000494:pharmacology; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D007976:Leupeptins; D061988:Proteasome Inhibitors; D020932:Nerve Growth Factor; D020917:Receptor, trkA; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C001277:geldanamycin