Research Description
HEAT-SHOCK PROTEINS AND GENES
Summary: My laboratory investigates the heat-shock protein Hsp70, its encoding genes, and its regulation in Drosophila as a model system for understanding evolutionary adaptation. Hsp70 is a molecular chaperone that deters stress-induced protein aggregation, but has numerous other functions. Hsp70 is necessary for full-strength tolerance (in terms of survival, normal development, normal function) of high temperature. Such tolerance is critical in nature, where non-adult Drosophila undergo harmful to lethal high temperatures. In nature, Drosophila populations vary in stress tolerance and Hsp70 levels. Our current major focus is on understanding the genomic basis for this variation. The number of hsp70 gene copies and evolution of the hsp70 coding sequence are partial or inadequate explanations. Evidently cis-regulatory regions such as proximal promoters underlie intraspecific variation in Hsp70 levels. Repeated insertion of mobile genetic elements into these promoters is a recurrent mechanism of evolution.
Why are heat-shock proteins important?
Are heat-shock proteins important in nature?
How is natural variation in Hsp70 expression encoded at the genomic level?
Why are heat-shock proteins important?
At least for Hsp70 in Drosophila, heat-shock proteins are important for inducible
thermotolerance.
|
|
Drosophila larvae exposed to a mild heat shock are able to
withstand a severe heat shock and pupate successfully (LEFT). Drosophila larvae exposed directly to a severe heat shock
without pretreatment die (RIGHT). Such inducible thermotolerance is
correlated with the expression of heat-shock proteins. [Images courtesy of
Juliana H. Feder] |
We know this from
experimental studies of Drosophila
that have been genetically engineered to differ in Hsp70 protein levels. To
date, these include allelic series of hsp70 gene copy number created by homologous
recombination, hsf [heat-shock
factor, the transcription factor that coordinately regulates the expression of
all heat-shock genes] knockout and rescue strains, and metallothionein-hsp70 fusions, which enable inducible gut-specific Hsp70
expression off of a heterologous promoter.
For example, strains with
extra copies of the hsp70 gene [created
in the laboratory of Sue
Lindquist] express more Hsp70 protein and have greater inducible
thermotolerance (red arrow) than do sister strains from which the extra copies
have been excised (yellow arrow).
|
|
|
Stress on pre-adult stages
results in developmental abnormalities in adults (above left). Extra copies of hsp70 can reduce the
frequency of these abnormalities (above right).
In a mouse brain slice
model, modulation of glutamatergic and glycinergic miniature potentials fails
as temperature increases. Addition
of Hsp70 to the buffer bathing the brain slice significantly reduces this
failure.
But too much Hsp70 or
prolonged exposure to Hsp70 can be harmful. Hsp70's other functions
may include interactions with apoptosis, signaling pathways, transcription
factors, cell cycle, intracellular calcium, and membrane conductance - and
these functions require stringent regulation of Hsp70 level. As a result, engineering increased
Hsp70 levels can increase mortality:
For a complete list of
laboratory publications on the above topics, go to