HSF1-dependent and -independent regulation of the mammalian in vivo heat shock response and its impairment in Huntington's disease mouse models

Abstract

The heat shock response (HSR) is a mechanism to cope with proteotoxic stress by inducing the expression of molecular chaperones and other heat shock response genes. The HSR is evolutionarily well conserved and has been widely studied in bacteria, cell lines and lower eukaryotic model organisms. However, mechanistic insights into the HSR in higher eukaryotes, in particular in mammals, are limited. We have developed an in vivo heat shock protocol to analyze the HSR in mice and dissected heat shock factor 1 (HSF1)-dependent and -independent pathways. Whilst the induction of proteostasis-related genes was dependent on HSF1, the regulation of circadian function related genes, indicating that the circadian clock oscillators have been reset, was independent of its presence. Furthermore, we demonstrate that the in vivo HSR is impaired in mouse models of Huntington’s disease but we were unable to corroborate the general repression of transcription that follows a heat shock in lower eukaryotes.

Heat Shock Factor 1 Predicts Poor Prognosis of Gastric Cancer

“…HSPs, such as HSP27, HSP70, and HSP90, are important chaperone proteins that promote proper folding, transportation, and degradation of proteins within cells. 9 10 11 12 HSF1 activation is repressed by interaction with overexpressed HSP in non-tumor cells. 9 10 11 12 13 However, this feedback inhibition may be ineffective in tumor cells.…”

“… 9 This pro-malignant activity is induced upon the binding of HSF1 to the promoters and the subsequent initiation of the expression of certain genes independent of heat shock. 11 14 Several studies have demonstrated that HSF1 is overexpressed in solid tumor cancers, including esophageal squamous cell, breast, hepatocellular, osteosarcoma, non-small cell lung, and pancreatic cancer. 15 16 17 18 Furthermore, evidence implies that the elevated expression of HSF1 is correlated with poor survival in patients with cancer.…”

Topokaryotyping demonstrates single cell variability and stress dependent variations in nuclear envelope associated domains

“…Consistently with the previous studies reporting the heat-induced changes in NE (50), we observed that treatment with heat shock decreases NE-association of der19 chromosome domains in a reversible dose-dependent manner. It has been reported that the heat shock proteins are induced in response to elevated temperature (51) together with the increased association of nuclear proteins with the nuclear matrix (52). It is therefore, attractive to speculate that denaturation and aggregation of nuclear proteins affects the physical properties of chromatin, possibly affecting chromatin-NE associations.…”

Topokaryotyping demonstrates single cell variability and stress dependent variations in nuclear envelope associated domains

“…Consistently with the previous studies reporting the heat-induced changes in NE (50), we observed that treatment with heat shock decreases NE-association of der19 chromosome domains in a reversible dose-dependent manner. It has been reported that the heat shock proteins are induced in response to elevated temperature (51) together with the increased association of nuclear proteins with the nuclear matrix (52). It is therefore, attractive to speculate that denaturation and aggregation of nuclear proteins affects the physical properties of chromatin, possibly affecting chromatin-NE associations.…”