JNK phosphorylates the HSF1 transcriptional activation domain: role of JNK in the regulation of the heat shock response.
The role of c-Jun NH2-terminal kinase (JNK) signaling cascade in the stress-inducible phosphorylation of heat shock factor 1 (HSF1) was investigated using known agonists and antagonists of JNK. We showed that treatment of HeLa cells with MG132, a proteasome inhibitor and known INK activator, caused the transcriptional activation domain of HSF1 to be targeted and phosphorylated by JNK2 in vivo. Dose-response and time course studies of the effects of heat shock and anisomycin treatment showed a close correlation of the activation of JNK and hyperphosphorylation of HSF1. SB203580 inhibited INK at the 100 microM concentration and significantly reduced the amount of hyperphosphorylated HSF1 upon heat shock or anisomycin treatment. SB203580 and dominant-negative JNK suppress hsp70 promoter-driven reporter gene expression selectively at 45 degrees C but not at 42 degrees C heat stress, suggesting that JNK would be preferentially associated with the protective heat shock response against severe heat stress. The possibility that JNK-mediated phosphorylation of HSF1 may selectively stabilize the HSF1 protein and confers protection to cells under conditions of severe stress is discussed.
Park
J
J
Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway 08854-8082, USA. JPARK@molbio.princeton.edu
Liu
A Y
AY
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006367:HeLa Cells / Q000187:drug effects / Q000201:enzymology; D000076249:Heat Shock Transcription Factors; D006358:Hot Temperature; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D007976:Leupeptins / Q000494:pharmacology; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000201:enzymology* / Q000235:genetics; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D007093:Imidazoles; D007527:Isoenzymes; D007976:Leupeptins; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000841:Anisomycin; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C093642:SB 203580; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde