MECHANISM OF REGULATION OF HEAT SHOCK GENE EXPRESSION

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Processes such as embryonic development, cell differentiation or adaptation of cells to new environments all involve changes in the levels of expression of various genes. Our understanding of these processes is therefore critically dependent on our knowledge of the molecular mechanisms of gene regulation. In the research described in this proposal, Drosophila heat shock protein genes are used as model system for studying aspects of gene regulation in several of the above processes. Heat shock protein genes appear to occur in every living organism, and the structures of the protein products of some of them are highly conserved. The genes are expressed at exceedingly high levels at elevated temperature and typically at very low levels at the normal, physiological temperature of an organism, and one role of their products appears to be to protect cells against stress-induced damage. The genes are also expressed at different stages of normal development. Since at least one of the genes is activated by different transforming genes and since the human genes are maximally active at temperatures that are reached during periods of high fever or during hyperthermic treatments of cancers, information about these genes and their regulation are not only of general interest but may even become of practical importance in medicine. Hybrid genes in which the E. coli Beta-galactosidase coding region has been placed under the control of linked heat shock protein gene promoter sequences have been constructed. These hybrid genes can be introduced into Drosophila cells where, when activated, they direct the synthesis of Beta-galactosidase. The heat-induced expression of two and the developmental regulation of one of these hybrid genes and of derivatives of the genes containing promoter segments that have been altered by in vitro sequence manipulation will be examined in a suitable Drosophila tissue culture system and in the developing organism (hybrid genes are introduced into the germline by P-element-mediated transformation). This work will define the signal sequences responsible for the developmental and heat-induced activation of heat shock protein genes. Experiments to identify novel factors involved in the heat and developmental control of heat shock gene expression are proposed.