The Heat-Shock Response 
Susan L. Lindquist, Ph.D. — Investigator 
Dr. Lindquist is also Professor in the Department of Molecular Genetics and Cell Biology and in the Com- 
mittees on Developmental Biology and Genetics at the University of Chicago. She received her B.S. degree 
in microbiology from the University of Illinois, where she worked with John Drake on bacteriophage T4. 
Her dissertation research was done with Matthew Meselson at Harvard University, where she began her 
work on the heat-shock response. She continued this work during her postdoctoral research with Hewson 
Swift at the University of Chicago. 
THE causes of heat-induced lethality and the 
mechanisms employed by cells to protect 
themselves from heat damage are poorly under- 
stood. Over the past decade, a great deal of re- 
search has focused on a small group of highly 
conserved proteins, the heat-shock proteins 
(HSPs). These proteins are induced in response 
to temperature elevation and a wide variety of 
other stresses. This remarkable response is the 
most highly conserved genetic induction known, 
which underscores its fundamental importance 
in biology. Archaeobacteria, eubacteria, plants, 
and animals all produce similar proteins. Several 
of these proteins show very high levels of conser- 
vation, with 40-50 percent amino acid identity 
between the proteins of human cells and bacte- 
rial cells. 
Much indirect evidence suggests that the HSPs 
are instrumental in protecting cells and organ- 
isms from lethality at extreme temperatures. For 
example, pretreatments at moderately elevated 
temperatures, which induce the synthesis of 
HSPs, result in tolerance to much higher tempera- 
tures. The kinetics of HSP induction closely paral- 
lel the kinetics of thermotolerance induction, 
and the decay of HSPs from the cell closely paral- 
lels the decline in thermotolerance. Moreover, 
HSP functions are not limited to conditions of 
high temperature. They are induced by many 
other stresses, including anoxia and reoxygena- 
tion, heavy metal ions, ethanol, and inhibitors of 
respiration or oxidative phosphorylation. In gen- 
eral, exposure to one form of stress provides toler- 
ance to another, suggesting that the proteins have 
broad protective roles. Studies of the heat-shock 
response are, therefore, of practical interest. 
(The development of crop plants with extended 
heat tolerance, for example, would be of enor- 
mous benefit to agricultural productivity.) 
HSPs are of particular interest to human biol- 
ogy and medicine, for four reasons. 1) Studies of 
cultured cells in vitro and of tumors in vivo dem- 
onstrate that many cancer cells are more readily 
killed by heat than are untransformed cells. For 
this reason, hyperthermia, in conjunction with 
radiation and chemotherapy, is emerging as an 
important new tool in cancer therapy. 2) High 
temperatures are associated with a number of de- 
velopmental anomalies in a wide variety of plants 
and animals, including spina bifida in humans. In 
those organisms that have been subjected to ex- 
perimental manipulation, mild preheat treat- 
ments, which induce the HSPs, provide protec- 
tion. 3) The induction of HSPs is associated with 
a variety of human pathological states, including 
strokes, heart attacks, and kidney disease. Interest 
in the proteins includes both their putative pro- 
tective functions in affected tissues and the possi- 
bility of quantifying them as disease markers. 4) 
The proteins interact with and potentiate the 
function of many other proteins in the cell. 
As important as these pragmatic concerns may 
be, most studies of the heat-shock response, in- 
cluding those in my laboratory, have been moti- 
vated by other considerations. Initially the re- 
sponse was exploited as a model system to study 
the cellular mechanisms involved in regulating 
protein synthesis. Because induction of the pro- 
teins is required for survival, a number of sophis- 
ticated mechanisms are employed to ensure that 
the proteins will be produced as rapidly as possi- 
ble after exposure to stress. Thus studies of the 
response have provided fundamental insights on 
the nature of nuclear and cytoplasmic regulation 
in both eukaryotes and prokaryotes. 
The recent discovery that the HSPs, or their 
close relatives, play vital roles in the cell at nor- 
mal temperatures has opened up a whole new 
field of investigation. The specific molecular 
functions of the HSPs are only beginning to be 
elucidated, but they appear to play a role in a 
remarkable number of basic cellular processes, 
among them secretion, signal transduction, and 
ribosome assembly. Determining the roles these 
proteins play in these processes will provide fun- 
damental insights in cell biology. 
We are investigating the regulation and the 
function of the HSPs. Our research focuses on the 
yeast Saccharomyces cerevisiae and the fruit fly 
Drosophila melanogaster, because techniques 
of genetic manipulation and molecular analysis 
are so advanced in them. For the past few years 
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