MECHANISM OF REGULATION OF HEAT SHOCK GENE EXPRESSION

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Transcription of typical heat shock protein (hsp) genes is enhanced drastically be heat and other stressors, and, in some cases, at distinct stages of development. Hsps are found to participate in basic biological mechanisms and have also been linked to immunological processes and pathological conditions, mobilizing intense interest by the medical community. It is therefore important to better understand the properties of hsps and the regulation of their expression. Stress regulation is mediated by heat shock transcription factor HSF, a protein containing three leucine zippers (LZs) and , in mammalian cells, a C-terminal homology region (CTR). In unstressed human cells, H2SF1 is present in an ill- defined, inactive form incapable of DNA binding. Upon stress HSF1 homotrimerizes, acquiring DNA binding and transcriptional ability. Heat and other stressful conditions result in the accumulation of nonfolded proteins that may serve as the common signal triggering HSF activation. One of the hsps, most likely an hsp70-type protein, senses the level of stress and may, directly or indirectly, negatively regulate HSF activity. Continuation of studies with human HSF1 is proposed to 1) test the hypothesis that trimerization is the master regulatory event that controls DNA binding ability, nuclear transport and transcriptional activity of hSF1 and demonstrate that trimerization is prevented in unstressed cells by protein-protein interactions involving all three LZs as well as the CTR region, 2) provide evidence that regulation of trimerization is based on reversible interactions of hsp70 with some of the latter motifs, 3) examine whether phosphorylation plays a role in HSF1, activation, and 4) study in vitro the process of HSF1 inactivation following stress. Drosophila hsp27 and 23 genes are active in late third instar larvae and are regulated by ecdysterone receptor (EcR). The hsp27 gene behaves as a primary, and the hsp23 gene as a secondary hormone-responsive gene. This Differential regulation is mediated through binding sites for EcR in the promoters of the two genes and may be studied as a novel paradigm for early v. late gene regulation in Drosophila larvae. We propose to attempt the elucidation of the mechanism underlying this differential regulation.