Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter

2019 ◽  
Vol 109 (4) ◽  
pp. 362-373
Author(s):  
Denis Ciato ◽  
Ran Li ◽  
Jose Luis Monteserin Garcia ◽  
Lilia Papst ◽  
Sarah D’Annunzio ◽  
...  
Keyword(s):  
Heat Shock ◽  
Clinical Features ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Primary Cultures ◽  
Heat Shock Protein 90 ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Promising Treatment ◽  
Acth Secreting

Background: Cushing’s disease (CD) is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. They express high levels of heat shock protein 90 and heat shock factor 1 (HSF1) in comparison to the normal tissue counterpart, indicating activated cellular stress. Aims: Our objectives were: (1) to correlate HSF1 expression with clinical features and hormonal/radiological findings of CD, and (2) to investigate the effects of HSF1 inhibition as a target for CD treatment. Patients/Methods: We examined the expression of total and pSer326HSF1 (marker for its transcriptional activation) by Western blot on eight human CD tumours and compared to the HSF1 status of normal pituitary. We screened a cohort of 45 patients with CD for HSF1 by immunohistochemistry and correlated the HSF1 immunoreactivity score with the available clinical data. We evaluated the effects of HSF1 silencing with RNA interference and the HSF1 inhibitor KRIBB11 in AtT-20 cells and four primary cultures of human corticotroph tumours. Results: We show that HSF1 protein is highly expressed and transcriptionally active in CD tumours in comparison to normal pituitary. The immunoreactivity score for HSF1 did not correlate with the typical clinical features of the disease. HSF1 inhibition reduced proopiomelanocortin (Pomc) transcription in AtT-20 cells. The HSF1 inhibitor KRIBB11 suppressed ACTH synthesis from 75% of human CD tumours in primary cell culture. This inhibitory action on Pomc transcription was mediated by increased glucocorticoid receptor and suppressed Nurr77/Nurr1 and AP-1 transcriptional activities. Conclusions: These data show that HSF1 regulates POMC transcription. Pharmacological targeting of HSF1 may be a promising treatment option for the control of excess ACTH secretion in CD.

scholarly journals Intramolecular Repression of Mouse Heat Shock Factor 1

1998 ◽  
Vol 18 (2) ◽  
pp. 906-918 ◽  
Author(s):  
Thomas Farkas ◽  
Yulia A. Kutskova ◽  
Vincenzo Zimarino
Keyword(s):  
Heat Shock ◽  
Transcriptional Activation ◽  
Mammalian Cells ◽  
Coiled Coil ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Reticulocyte Lysate ◽  
Heptad Repeats ◽  
Intramolecular Mechanism

ABSTRACT The pathway leading to transcriptional activation of heat shock genes involves a step of heat shock factor 1 (HSF1) trimerization required for high-affinity binding of this activator protein to heat shock elements (HSEs) in the promoters. Previous studies have shown that in vivo the trimerization is negatively regulated at physiological temperatures by a mechanism that requires multiple hydrophobic heptad repeats (HRs) which may form a coiled coil in the monomer. To investigate the minimal requirements for negative regulation, in this work we have examined mouse HSF1 translated in rabbit reticulocyte lysate or extracted from Escherichia coli after limited expression. We show that under these conditions HSF1 behaves as a monomer which can be induced by increases in temperature to form active HSE-binding trimers and that mutations of either HR region cause activation in both systems. Furthermore, temperature elevations and acidic buffers activate purified HSF1, and mild proteolysis excises fragments which form HSE-binding oligomers. These results suggest that oligomerization can be repressed in the monomer, as previously proposed, and that repression can be relieved in the apparent absence of regulatory proteins. An intramolecular mechanism may be central for the regulation of this transcription factor in mammalian cells, although not necessarily sufficient.

scholarly journals Heat Shock Factor 1 Represses Ras-induced Transcriptional Activation of the c-fosGene

1997 ◽  
Vol 272 (43) ◽  
pp. 26803-26806 ◽  
Author(s):  
Changmin Chen ◽  
Yue Xie ◽  
Mary Ann Stevenson ◽  
Philip E. Auron ◽  
Stuart K. Calderwood
Keyword(s):  
Heat Shock ◽  
Transcriptional Activation ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1

Poly(ADP-ribosyl)ation regulates heat shock factor-1 activity and the heat shock response in murine fibroblasts

2006 ◽  
Vol 84 (5) ◽  
pp. 703-712 ◽  
Author(s):  
Silvia Fossati ◽  
Laura Formentini ◽  
Zhao-Qi Wang ◽  
Flavio Moroni ◽  
Alberto Chiarugi
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Heat Shock Factor ◽  
Binding Motif ◽  
Heat Shock Factor 1 ◽  
Shock Response ◽  
Parp 1

Poly(ADP-ribose) polymerase-1 (PARP-1)-dependent poly(ADP-ribose) formation is emerging as a key regulator of transcriptional regulation, even though the targets and underlying molecular mechanisms have not yet been clearly identified. In this study, we gathered information on the role of PARP-1 activity in the heat shock response of mouse fibroblasts. We show that DNA binding of heat shock factor (HSF)-1 was impaired by PARP-1 activity in cellular extracts, and was higher in PARP-1−/− than in PARP-1+/+ cells. No evidence for HSF-1 poly(ADP-ribosyl)ation or PARP-1 interaction was found, but a poly(ADP-ribose) binding motif was identified in the transcription factor amino acid sequence. Consistent with data on HSF-1, the expression of heat-shock protein (HSP)-70 and HSP–27 was facilitated in cells lacking PARP-1. Thermosensitivity, however, was higher in PARP-1−/− than in PARP-1+/+ cells. Accordingly, we report that heat-shocked PARP-1 null fibroblasts showed an increased activation of proapoptotic JNK and decreased transcriptional efficiency of prosurvival NF-κB compared with wild-type counterparts. The data indicate that poly(ADP-ribosyl)ation finely regulates HSF-1 activity, and emphasize the complex role of PARP-1 in the heat-shock response of mammalian cells.

An atmospheric electrophile activates heat shock factor 1 through S-arylation of heat shock protein 90

2016 ◽  
Vol 258 ◽  
pp. S253
Author(s):  
R. Hirose ◽  
T. Unoki ◽  
Y. Abiko ◽  
Y. Shinkai ◽  
R. Sha ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1

scholarly journals Transcriptional Activation Domains of Human Heat Shock Factor 1 Recruit Human SWI/SNF

2001 ◽  
Vol 21 (17) ◽  
pp. 5826-5837 ◽  
Author(s):  
E. Kelly Sullivan ◽  
Christine S. Weirich ◽  
Jeffrey R. Guyon ◽  
Saı̈d Sif ◽  
Robert E. Kingston
Keyword(s):  
Heat Shock ◽  
Chromatin Remodeling ◽  
Transcriptional Activation ◽  
Atp Hydrolysis ◽  
Heat Shock Factor ◽  
Transcriptional Elongation ◽  
Heat Shock Factor 1 ◽  
Transcriptional Initiation ◽  
Atpase Subunit ◽  
Activation Domains

ABSTRACT Chromatin remodeling complexes such as SWI/SNF use the energy of ATP hydrolysis to remodel nucleosomal DNA and increase transcription of nucleosomal templates. Human heat shock factor one (hHSF1) is a tightly regulated activator that stimulates transcriptional initiation and elongation using different portions of its activation domains. Here we demonstrate that hHSF1 associates with BRG1, the ATPase subunit of human SWI/SNF (hSWI/SNF) at endogenous protein concentrations. We also show that hHSF1 activation domains recruit hSWI/SNF to a chromatin template in a purified system. Mutation of hHSF1 residues responsible for activation of transcriptional elongation has the most severe effect on recruitment of SWI/SNF and association of hHSF1 with BRG1, suggesting that recruitment of chromatin remodeling activity might play a role in stimulation of elongation.

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