Signal Transduction Pathways Leading to Heat Shock Transcription

Abstract

Heat shock proteins (HSP) are essential for intracellular protein folding during stress and protect cells from denaturation and aggregation cascades that can lead to cell death. HSP genes are regulated at the transcriptional level by heat shock transcription factor 1 (HSF1) that is activated by stress and binds to heat shock elements in HSP genes. The activation of HSF1 during heat shock involves conversion from an inert monomer to a DNA binding trimer through a series of intramolecular folding rearrangements. However, the trigger for HSF1 at the molecular level is unclear and hypotheses for this process include reversal of feedback inhibition of HSF1 by molecular chaperones and heat-induced binding to large non-coding RNAs. Heat shock also causes a profound modulation in cell signaling pathways that lead to protein kinase activation and phosphorylation of HSF1 at a number of regulatory serine residues. HSP genes themselves exist in an accessible chromatin conformation already bound to RNA polymerase II. The RNA polymerase II is paused on HSP promoters after transcribing a short RNA sequence proximal to the promoter. Activation by heat shock involves HSF1 binding to the promoter and release of the paused RNA polymerase II followed by further rounds of transcriptional initiation and elongation. HSF1 is thus involved in both initiation and elongation of HSP RNA transcripts. Recent studies indicate important roles for histone modifications on HSP genes during heat shock. Histone modification occurs rapidly after stress and may be involved in promoting nucleosome remodeling on HSP promoters and in the open reading frames of HSP genes. Understanding these processes may be key to evaluating mechanisms of deregulated HSP expression that plays a key role in neurodegeneration and cancer.

Toll-like Receptor Agonists and Febrile Range Hyperthermia Synergize to Induce Heat Shock Protein 70 Expression and Extracellular Release

“…These results suggest that p38 (primarily p38␣) or one of its downstream targets participates in LPS-induced phosphorylation of histone H3 on the Hsp70 chromatin, recruitment of HSF1, and transcriptional activation of Hsp70. However, we have not excluded the contribution of additional HSF1 and histone modifications including HSF1 sumoylation (62,63) and histone acetylation and methylation (42,49,54,64).…”

“…Because the transcriptional activation of Hsp genes is regulated by the stress-activated transcription factor, HSF1, which itself is regulated by post-translational modification including phosphorylation (18,48,49), we analyzed whether the TLR agonists stimulated post-translational modification of HSF1. We found that RAW cells stimulated with TLR1/2 and TLR 4 agonists at 37°C caused a distinct shift in HSF1 mobility on SDS and on two-dimensional gels (Fig.…”

The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma

“…PI3K inhibition also caused strong decreases in the level of Hsp27, another HSF1-regulated heat shock protein ( Figure 4). Because GSK3b has been reported to have a role in the stability of HSF1 [26][27][28] we tested whether dephosphorylated (i.e. active) GSK3b might be involved in the down-regulation of HSF1.…”

Heat shock protein 60 and chromatin assembly factor-1 mRNA levels in hepatitis C virus-related hepatocellular carcinoma and clinical significance

“…5 HSPs are stress proteins whose synthesis is exaggerated by proteotoxic stresses such as heat shock. 6 The superfamily members, based on their molecular weight, include HSP90, HSP70, HSP60, HSP40 and small HSPs including HSP27. 7 HSP60, a typical mitochondrial chaperone, is associated with progression of diverse cancers.…”