Manipulation of protein kinases reveals different mechanisms for upregulation of heat shock proteins in motor neurons and non-neuronal cells.
Motor neurons have a high threshold for induction of heat shock proteins (Hsps) in response to stress, a property associated with impaired ability to activate heat shock transcription factor 1 (Hsf1). Hyperphosphorylation of Hsf1 has been established as a requirement for transactivation of heat shock genes. This study demonstrated that the impaired heat shock response in motor neurons is not due to altered phosphorylation of Hsf1 by kinases previously shown to affect activation of Hsf1 in other cells (PKC, GSK3beta, ERK1, CaMKIIalpha). However, a constitutively active form of CaMKIV induced robust expression of Hsp70, as well as transcription of a GFP reporter gene driven by the human inducible Hsp70 promoter in unstressed motor neurons, but not in mouse embryonic fibroblasts. The results point to novel mechanisms of activation of heat shock genes in motor neurons that have relevance to exploitation of endogenous stress responses therapeutically.
Taylor
David M
DM
Montreal Neurological Institute, McGill University, 3801 University St., Montreal, Quebec, Canada H3A 2B4.
De Koninck
Paul
P
Minotti
Sandra
S
Durham
Heather D
HD
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D017930:Genes, Reporter / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response / Q000502:physiology*; D051379:Mice; D009046:Motor Neurons / Q000201:enzymology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D013312:Stress, Physiological / Q000201:enzymology* / Q000503:physiopathology; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D011494:Protein Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D011493:Protein Kinase C; C517683:CAMK4 protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse; D038362:Glycogen Synthase Kinase 3