title: Prion formation correlates with activation of translation-regulating protein 4E-BP and neuronal transcription factor Elk1.
abstract: Cellular mechanisms play a role in conversion of the normal prion protein PrP(C) to the disease-associated protein PrP(Sc). The cells provide not only PrP(C), but also still largely undefined factors required for efficient prion replication. Previously, we have observed that interference with ERK and p38-JNK MAP kinase pathways has opposing effects on the formation of prions indicating that the process is regulated by a balance in intracellualar signaling pathways. In order to obtain a "flow-chart" of such pathways, we here studied the activation of MEK/ERK and mTORC1 downstream targets in relation to PrP(Sc) accumulation in GT1-1 cells infected with the RML or 22L prion strains. We show that inhibition of mTORC1 with rapamycin causes a reduction of PrP(Sc) accumulation at similar low levels as seen when the interaction between the translation initiation factors eIF4E and eIF4G downstream mTORC1 is inhibited using 4EGI-1. No effect is seen following the inhibition of molecules (S6K1 and Mnk1) that links MEK/ERK signaling to mTORC1-mediated control of translation. Instead, stimulation (high [KCl] or [serum]) or inhibition (MEK-inhibitor) of prion formation is associated with increased or decreased phosphorylation of the neuronal transcription factor Elk1, respectively. This study shows that prion formation can be modulated by translational initiating factors, and suggests that MEK/ERK signaling plays a role in the conversion of PrP(C) to PrP(Sc) via an Elk1-mediated transcriptional control. Altogether, our studies indicate that prion protein conversion is under the control of intracellular signals, which hypothetically, under certain conditions may elicit irreversible responses leading to progressive neurodegenerative diseases.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Elin K
authors.initials: EK
authors.lastname: Allard
authors.forename: Mirjana
authors.initials: M
authors.lastname: Grujic
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fisone
authors.forename: Krister
authors.initials: K
authors.lastname: Kristensson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039642:Eukaryotic Initiation Factors; D006657:Histones / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011328:Prions / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014162:Transfection; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002070:Butadienes; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; C494113:Elk1 protein, mouse; D004791:Enzyme Inhibitors; D039642:Eukaryotic Initiation Factors; D006657:Histones; D046912:Multiprotein Complexes; D009570:Nitriles; D010750:Phosphoproteins; D011328:Prions; C113580:U 0126; D050807:ets-Domain Protein Elk-1; D011189:Potassium Chloride; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020123:Sirolimus
keywords: 4E-BP; BDNF; BrdU; CGP 57380; DMSO; ERK; GT1-1 cells; Infections; Intracellular signaling; MAP; MAP kinase-interacting kinases; MEK; MEK-inhibitor (1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene ethanolate); Mnk1-inhibitor N3-(4-fluorophenyl)-1h-pyrazolo[3,4-d]pyrimidine-3,4-diamine; Mnk1/2; Nervous system; Neurodegenerative diseases; PF-4708671; PrP(C); PrP(Sc); Prions; S6K1; S6K1-inhibitor 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole; S6rp; TSC; U0126; brain-derived neurotrophic factor; bromodeoxiuridine; dimethyl sulfoxide; disease-associated prion protein; eIF4E; eukaryotic initiation factor 4E; eukaryotic initiation factor 4E binding protein; extracellular signal-regulated kinase; immortalized hypothalamic gonadotropin-releasing hormone neurons; leupeptin; leupeptin hydrochloride; mTORC1; mammalian target of rapamycin complex 1; mitogen-activated protein; mitogen-activated protein kinase kinase; normal cellular prion protein; p70 ribosomal S6 Kinase 1; ribosomal protein S6; tuberous sclerosis complex