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 
Committees 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 graduate research was done with Matthew Meselson at Harvard University, where 
she began her studies 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 that cells employ 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 mole- 
cules, the heat-shock proteins (HSPs). These are 
induced in response to temperature elevation 
and a wide variety of other stresses. No known 
genetic induction is more highly conserved in 
evolution, which underscores its fundamental 
importance in biology. Archaeobacteria, eubac- 
teria, plants, and animals all produce similar pro- 
teins. Several of these proteins show very high 
levels of conservation, commonly with 40-50 
percent amino acid identity between HSPs of hu- 
man and bacterial cells. 
The induction of HSPs 1) allows cells to grow 
at the upper end of their normal growth range, 2) 
potentiates survival during long exposures to tem- 
peratures just beyond the normal growth range, 
and 3) protects cells from lethality at tempera- 
ture extremes. Interestingly, different proteins 
are required for each of these functions. HSPs 
also protect cells from heavy metal ions, ethanol, 
and many other sources of stress. The importance 
of different proteins in protecting against differ- 
ent forms of stress also varies. 
The stress inductions of HSPs are of interest to 
human biology and medicine for several reasons. 
First, studies of cultured cells in vitro and of tu- 
mors in vivo demonstrate that many cancer cells 
are more readily killed by heat than are untrans- 
formed cells. For this reason, hyperthermia, in 
conjunction with radiation and chemotherapy, is 
emerging as an important new tool in cancer ther- 
apy. Second, high temperatures are associated 
with a number of developmental anomalies in a 
wide variety of plants and animals, including 
spina bifida in humans. In those organisms that 
have been subjected to experimental manipula- 
tion, mild preheat treatments, which induce the 
HSPs, provide protection. Third, the induction of 
HSPs is associated with a variety of human patho- 
logical states, including strokes, heart attacks, 
and kidney disease. Interest in the proteins in- 
cludes both their putative protective functions in 
affected tissues and the possibility of quantifying 
them as disease markers. Fourth, the proteins in- 
teract with and potentiate the function of many 
other vital proteins in the cell. 
The heat-shock response also provides a superb 
model system in which to study the cellular 
mechanisms involved in regulating protein syn- 
thesis. Because HSPs are required for survival, a 
number of regulatory mechanisms are employed 
to ensure that the proteins will be produced as 
rapidly as possible after exposure to stress. Thus 
studies of the response have provided funda- 
mental insights on the nature of nuclear and cy- 
toplasmic regulation in both eukaryotes and 
prokaryotes. 
The recent discovery that the HSPs themselves, 
or close relatives produced at normal tempera- 
tures, play vital roles during normal growth and 
development has opened up a whole new field of 
investigation. The specific molecular functions 
of the HSPs are only beginning to be elucidated, 
but they play a role in a remarkable number of 
basic cellular processes, including secretion, sig- 
nal transduction, and ribosome assembly. Deter- 
mining the roles that HSPs play in these processes 
will provide fundamental insights in cell biology. 
We are investigating the regulation and func- 
tion of these proteins. Our research focuses on 
the yeast Saccharomyces cerevisiae and the fruit 
fly Drosophila melanogaster, because tech- 
niques of genetic manipulation and molecular 
analysis are so advanced in these organisms. For 
the past few years our investigations of the regula- 
tion of the response have concentrated on post- 
transcriptional mechanisms that are employed to 
maximize the synthesis of the HSPs during heat 
shock or to shut off synthesis after heat shock. 
Tom McGarry and Bob Petersen found that 
heat-shock mRNAs in Drosophila cells are prefer- 
entially translated during heat shock by virtue of 
sequences in their 5'-untranslated leaders and are 
preferentially repressed during recovery through 
sequences in their 3'-untranslated tails. The latter 
sequences are shared by certain normal cellular 
messages, which have the common property of 
being rapidly degraded at normal temperatures. 
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