scholarly journals HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

2017 ◽  
Author(s):  
Toshiki Kijima ◽  
Thomas L. Prince ◽  
Megan L. Tigue ◽  
Kendrick H. Yim ◽  
Harvey Schwartz ◽  
...  
Keyword(s):  
Heat Shock ◽  
Transcriptional Activity ◽  
Transcriptional Response ◽  
Heat Shock Protein 90 ◽  
Heat Shock Factor 1 ◽  
Hsp90 Inhibitors ◽  
Dynamic Modulation ◽  
Proteotoxic Stress ◽  
Significant Prolongation

AbstractHeat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.

Abstract: P678 HEAT SHOCK PROTEIN 90 (HSP90) INHIBITORS ATTENUATE INFLAMATORY RESPONSES IN VITRO AND IN VIVO

2009 ◽  
Vol 10 (2) ◽  
pp. e864
Author(s):  
J Madrigal-Matute ◽  
ó López-Franco ◽  
L Blanco-Colio ◽  
B Muñoz-Garcia ◽  
P Ramos-Mozo ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitors

scholarly journals The Natural Osmolyte Trehalose Is a Positive Regulator of the Heat-Induced Activity of Yeast Heat Shock Transcription Factor

2006 ◽  
Vol 27 (4) ◽  
pp. 1505-1515 ◽  
Author(s):  
Laura K. Conlin ◽  
Hillary C. M. Nelson
Keyword(s):  
Heat Shock ◽  
Transcriptional Activity ◽  
Dynamic Range ◽  
Transcriptional Response ◽  
Mrna Levels ◽  
Adverse Conditions ◽  
Shock Response ◽  
Response To Stress ◽  
Low Levels

ABSTRACT In Saccharomyces cerevisiae, the intracellular concentration of trehalose increases rapidly in response to many environmental stresses, including heat shock. These high trehalose levels have been correlated with tolerance to adverse conditions and led to the model that trehalose functions as a chemical cochaperone. Here, we show that the transcriptional activity of Hsf1 during the heat shock response depends on trehalose. Strains with low levels of trehalose have a diminished transcriptional response to heat shock, while strains with high levels of trehalose have an enhanced transcriptional response to heat shock. The enhanced transcriptional response does not require the other heat-responsive transcription factors Msn2/4 but is dependent upon heat and Hsf1. In addition, the phosphorylation levels of Hsf1 correlate with both transcriptional activity and the presence of trehalose. These in vivo results support a new role for trehalose, where trehalose directly modifies the dynamic range of Hsf1 activity and therefore influences heat shock protein mRNA levels in response to stress.

Heat-shock protein 90 inhibition in autoimmunity to type VII collagen: evidence that nonmalignant plasma cells are not therapeutic targets

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6135-6142 ◽  
Author(s):  
Michael Kasperkiewicz ◽  
Ralf Müller ◽  
Rudolf Manz ◽  
Moritz Magens ◽  
Christoph M. Hammers ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Plasma Cells ◽  
Protein Biosynthesis ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Type Vii Collagen

Abstract Blocking heat-shock protein 90 (Hsp90) induces death of malignant plasma cells by activation of the unfolded protein response, a signaling pathway activated by accumulation of misfolded proteins within the endoplasmic reticulum. We hypothesized that nontransformed plasma cells are also hypersensitive to Hsp90 inhibition because of their high amount of protein biosynthesis. To investigate this hypothesis, 2 different Hsp90 inhibitors, the geldanamycin derivative 17-DMAG and the nontoxic peptide derivative TCBL-145, were applied to mice with experimental epidermolysis bullosa acquisita, an autoimmune bullous disease characterized by autoantibodies against type VII collagen of the dermal-epidermal junction. Both inhibitors ameliorated clinical disease of type VII collagen–immunized mice, suppressed auto-antibody production, and reduced dermal neutrophilic infiltrate. Interestingly, total plasma cell numbers, type VII collagen–specific plasma cells, and germinal center B cells were unaffected by anti-Hsp90 treatment in vivo. However, T-cell proliferation was potently inhibited, as evidenced by the reduced response of isolated lymph node cells from immunized mice to in vitro restimulation with anti-CD3/CD28 antibody or autoantigen in the presence of Hsp90 inhibitors. Our results suggest that Hsp90 blockade has no impact on normal or autoreactive plasma cells in vivo and indentify T cells as targets of anti-Hsp90 treatment in autoimmunity to type VII collagen.

scholarly journals Phosphorylation of Serine 303 Is a Prerequisite for the Stress-Inducible SUMO Modification of Heat Shock Factor 1

2003 ◽  
Vol 23 (8) ◽  
pp. 2953-2968 ◽  
Author(s):  
Ville Hietakangas ◽  
Johanna K. Ahlskog ◽  
Annika M. Jakobsson ◽  
Maria Hellesuo ◽  
Niko M. Sahlberg ◽  
...  
Keyword(s):  
Heat Shock ◽  
Phosphorylation Site ◽  
Stress Granules ◽  
Heat Shock Factor ◽  
Transcriptional Level ◽  
Heat Shock Factor 1 ◽  
Protection Mechanism ◽  
Sumo Modification

ABSTRACT The heat shock response, which is accompanied by a rapid and robust upregulation of heat shock proteins (Hsps), is a highly conserved protection mechanism against protein-damaging stress. Hsp induction is mainly regulated at transcriptional level by stress-inducible heat shock factor 1 (HSF1). Upon activation, HSF1 trimerizes, binds to DNA, concentrates in the nuclear stress granules, and undergoes a marked multisite phosphorylation, which correlates with its transcriptional activity. In this study, we show that HSF1 is modified by SUMO-1 and SUMO-2 in a stress-inducible manner. Sumoylation is rapidly and transiently enhanced on lysine 298, located in the regulatory domain of HSF1, adjacent to several critical phosphorylation sites. Sumoylation analyses of HSF1 phosphorylation site mutants reveal that specifically the phosphorylation-deficient S303 mutant remains devoid of SUMO modification in vivo and the mutant mimicking phosphorylation of S303 promotes HSF1 sumoylation in vitro, indicating that S303 phosphorylation is required for K298 sumoylation. This finding is further supported by phosphopeptide mapping and analysis with S303/7 phosphospecific antibodies, which demonstrate that serine 303 is a target for strong heat-inducible phosphorylation, corresponding to the inducible HSF1 sumoylation. A transient phosphorylation-dependent colocalization of HSF1 and SUMO-1 in nuclear stress granules provides evidence for a strictly regulated subnuclear interplay between HSF1 and SUMO.

scholarly journals DAXX interacts with heat shock factor 1 during stress activation and enhances its transcriptional activity

2004 ◽  
Vol 101 (12) ◽  
pp. 4100-4105 ◽  
Author(s):  
F. Boellmann ◽  
T. Guettouche ◽  
Y. Guo ◽  
M. Fenna ◽  
L. Mnayer ◽  
...  
Keyword(s):  
Heat Shock ◽  
Transcriptional Activity ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Stress Activation
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