it should be possible to manipulate the thermotoler- 
ance of complex multicellular organisms by deliber- 
ate genetic intervention. 
Regulation of HSP Expression 
The heat-shock response of Drosophila cells is 
particularly intense. Within minutes of a shift from 
25°C to 37°C, the entire pattern of protein synthe- 
sis is shifted from the production of normal cellular 
proteins to the production of HSPs. After heat shock, 
the full pattern of normal protein synthesis is re- 
stored. In the past year the laboratory's studies in 
Drosophila have concentrated on the regulation of 
hsp70 synthesis. This protein is almost undetectable 
in cells growing at normal temperatures but, after 
heat shock, it is the most abundantly synthesized 
protein. The hsp70 message is very stable during 
heat shock, but during recovery it is rapidly de- 
graded. This degradation appears to be highly spe- 
cific and occurs while most other cellular messages 
are being reactivated for translation. Degradation is 
also highly regulated and only occurs after a specific 
quantity of protein — a quantity appropriate to the 
particular level of heat stress applied to the cells — 
is produced. When the hsp70 message was ex- 
pressed at normal temperatures, from a heterolo- 
gous promoter, it was found to be very unstable. 
Thus heat shock inactivates a preexisting mecha- 
nism for degradation, and recovery restores it. 
The existence of so many regulatory mechanisms 
to ensure that hsp70 is expressed as rapidly as possi- 
ble after heat shock but is not expressed at normal 
temperatures suggested that hsp70 might be toxic 
at normal temperatures. Using heterologous pro- 
moters, the laboratory found that hsp70 blocks the 
growth of Drosophila cells. Remarkably, after sev- 
eral days of ectopic expression, cells resume growth 
and hsp70 is found sequestered in granule-like 
structures in the cell. These granules apparently rep- 
resent a new mechanism for regulating hsp70, in 
this case by controlling its activity rather than its 
level of expression. In the natural life cycle, this 
mechanism is used to regulate hsp70 activity. 
Within the first 3 h of embryonic life, hsp70 cannot 
be induced in embryos, and embryos are extremely 
sensitive to heat. From 3 to 6 h, hsp70 is inducible 
and embryos are capable of acquiring tolerance to 
heat. However, when embryos are allowed to re- 
cover at 25°C, they lose tolerance within a few min- 
utes. On a similar time scale, hsp70 coalesces into 
granules. The laboratory speculates that although 
hsp70 is beneficial for thermotolerance, it is toxic 
to the rapid cell divisions that occur in the early 
embryo. For this reason expression is prohibited in 
the earliest embryos, and the protein is rapidly se- 
questered in later embryos. Future experiments will 
test this hypothesis and explore the mechanisms 
that are employed in hsp70 sequestration. 
Dr. Lindquist is also Professor of Molecular 
Genetics and Cell Biology at the University of 
Chicago. 
Articles 
Feder, J.H., Rossi, J.M., Solomon, J., Solomon, N., 
and Lindquist, S. 1992. The consequences of ex- 
pressing hsp70 in Drosophila cells at normal tem- 
peratures. Genes Dev 6:\iQ2-\4\5. 
Lindquist, S. 1 992 . Won't you change partners and 
dance? Curr Biol 2:119-121. 
Parsell, D.A., Sanchez, Y., Stitzel, J.D., and Lind- 
quist, S. 1991. Hsp 1 04 is a highly conserved pro- 
tein with two essential nucleotide-binding sites. 
Nature 353:270-273. 
Sanchez, Y., Taulien, J., Borkovich, K.A., and Lind- 
quist, S. 1992. Hsp 104 is required for tolerance 
to many forms of stress. EMBO J 1 1 :2357-2364. 
Solomon, J.M., Rossi, J.M., Golic, K., McGarry, T., 
and Lindquist, S. 1991. Changes in hsp70 alter 
thermotolerance and heat-shock regulation in 
Drosophila. New Biol 3: 1 106-1 1 20. 
CONTROL OF CELL SURFACE OLIGOSACCHARIDE EXPRESSION 
John B. Lowe, M.D., Assistant Investigator 
During the past year. Dr. Lowe and his colleagues 
have continued to focus on the use of gene transfer 
systems to explore the functions of cell surface oli- 
gosaccharide determinants and on the isolation of 
additional mammalian glycosyltransferase genes. 
Work is also in progress to define the structures and 
expression patterns of murine glycosyltransferase 
genes, to provide a background for transgenic ani- 
mal studies designed to uncover functions of cell 
surface oligosaccharides during development. 
Mammalian cells express a diverse array of oligo- 
saccharide molecules on their surfaces. These mole- 
GENETICS 225 
