Chapter 268 - The Heat Shock Response and the Stress of Misfolded Proteins

Abstract

The heat shock response (HSR) is an inducible molecular response to a disruption of protein homeostasis that results in the elevated expression of cytoprotective genes that protect the proteome. The four general categories of environmental and physiological regulators of the HSR include: environmental stress, such as heat shock, amino acid analogs, drugs, oxidative stress, toxic chemicals, heavy metals, and pharmacologically active small molecules; cell growth and developmental conditions, including cell cycle, growth factors, development, differentiation, and activation by certain oncogenes; pathology and disease, such as neuroendocrine stress, tissue injury and repair, fever, inflammation, infection, ischemia and reperfusion, and cancer; and diseases of protein conformation including Huntington's disease, Alzheimer's disease, Parkinson's disease, and ALS. The HSR, through the elevated synthesis of molecular chaperones and proteases, responds rapidly and precisely to the intensity and duration of specific environmental and physiological stress signals to restore proteostasis and prevent further protein damage. Transient exposure to intermediate elevated temperatures or lower levels of chemical and environmental stress has cytoprotective effects against sustained, normally lethal, exposures to stress. HSFs are highly conserved and are required for normal cell growth and development in addition to their central importance in stress adaptation, survival, and disease. HSF1 as the principal stress activated factor binds to heat shock elements (HSEs) consisting of multiple contiguous inverted repeats of the pentamer sequence nGAAn located in the promoter regions of all heat shock responsive genes in eukaryotes.