Journal
ARCHIVES OF TOXICOLOGY
Volume 95, Issue 6, Pages 1943-1970Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-021-03070-8
Keywords
Heat shock protein (HSP); Molecular chaperones; Proteotoxic stress; Heat shock response (HSR); Proteostasis
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Funding
- Department of Radiation Oncology, BIDMC, Harvard Medical School
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Cells respond to protein-damaging stress by activating the Heat Shock Response (HSR), which plays a crucial role in determining cell survival or death. The modulation of HSR and its network have become attractive treatment strategies for neurodegenerative diseases and cancers. A detailed understanding of the mechanisms of HSR is necessary for the development of effective therapies, as important features of HSR continue to be uncovered.
Cells respond to protein-damaging (proteotoxic) stress by activation of the Heat Shock Response (HSR). The HSR provides cells with an enhanced ability to endure proteotoxic insults and plays a crucial role in determining subsequent cell death or survival. The HSR is, therefore, a critical factor that influences the toxicity of protein stress. While named for its vital role in the cellular response to heat stress, various components of the HSR system and the molecular chaperone network execute essential physiological functions as well as responses to other diverse toxic insults. The effector molecules of the HSR, the Heat Shock Factors (HSFs) and Heat Shock Proteins (HSPs), are also important regulatory targets in the progression of neurodegenerative diseases and cancers. Modulation of the HSR and/or its extended network have, therefore, become attractive treatment strategies for these diseases. Development of effective therapies will, however, require a detailed understanding of the HSR, important features of which continue to be uncovered and are yet to be completely understood. We review recently described and hallmark mechanistic principles of the HSR, the regulation and functions of HSPs, and contexts in which the HSR is activated and influences cell fate in response to various toxic conditions.
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