scholarly journals Cellular stress induces cancer stem-like cells through expression of DNAJB8 by activation of heat shock factor 1

2018 ◽  
Vol 109 (3) ◽  
pp. 741-750 ◽  
Author(s):  
Hiroki Kusumoto ◽  
Yoshihiko Hirohashi ◽  
Satoshi Nishizawa ◽  
Masamichi Yamashita ◽  
Kazuyo Yasuda ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cellular Stress ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1

scholarly journals Modulation of Heat Shock Factor 1 Activity through Silencing of Ser303/Ser307 Phosphorylation Supports a Metabolic Program Leading to Age-Related Obesity and Insulin Resistance

2018 ◽  
Vol 38 (18) ◽  
Author(s):  
Xiongjie Jin ◽  
Aijun Qiao ◽  
Demetrius Moskophidis ◽  
Nahid F. Mivechi
Keyword(s):  
Insulin Resistance ◽  
Heat Shock ◽  
Metabolic Diseases ◽  
Cellular Stress ◽  
Heat Shock Factor ◽  
Model Systems ◽  
Central Feature ◽  
Heat Shock Factor 1 ◽  
Age Related

ABSTRACT Activation of the adaptive response to cellular stress orchestrated by heat shock factor 1 (HSF1), which is an evolutionarily conserved transcriptional regulator of chaperone response and cellular bioenergetics in diverse model systems, is a central feature of organismal defense from environmental and cellular stress. HSF1 activity, induced by proteostatic, metabolic, and growth factor signals, is regulated by posttranscriptional modifications, yet the mechanisms that regulate HSF1 and particularly the functional significance of these modifications in modulating its biological activity in vivo remain unknown. HSF1 phosphorylation at both Ser303 (S303) and Ser307 (S307) has been shown to repress HSF1 transcriptional activity under normal physiological growth conditions. To determine the biological relevance of these HSF1 phosphorylation events, we generated a knock-in mouse model in which S303 and S307 were replaced with alanine (HSF1303A/307A). Our results confirmed that loss of phosphorylation in HSF1303A/307A cells and tissues increases protein stability but also markedly sensitizes HSF1 activation under normal and heat- or nutrient-induced stress conditions. Interestingly, the enhanced HSF1 activation in HSF1303A/307A mice activates a supportive metabolic program that aggravates the development of age-dependent obesity, fatty liver diseases, and insulin resistance. Thus, these findings highlight the importance of a posttranslational mechanism (through phosphorylation at S303 and S307 sites) of regulation of the HSF1-mediated transcriptional program that moderates the severity of nutrient-induced metabolic diseases.

scholarly journals Effects of neurohormonal stress and aging on the activation of mammalian heat shock factor 1.

1994 ◽  
Vol 269 (51) ◽  
pp. 32272-32278
Author(s):  
T W Fawcett ◽  
S L Sylvester ◽  
K D Sarge ◽  
R I Morimoto ◽  
N J Holbrook
Keyword(s):  
Heat Shock ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1

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.

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