One of the most perplexing discoveries in the past five years has been the finding that various environmental stresses such as heat shock, UV and X-irradiation, hypoxia and ischemia activate the same signaling pathways as those involved in cell growth, differentiation, development and transformation. These signaling cascades confer their information through positive or negative signals to transcription factors that regulate downstream genes. As such, phosphorylation and de-phosphorylation by protein kinases and phosphatases are an important mechanism of modulating transcription factor activity. One of the transcription factors that is regulated by diverse signal transduction pathways is the heat shock transcription factor-1 (HSF-1). Heat shock transcription factor (HSF-1) controls the expression of heat shock proteins (hsps), the molecular chaperones that are involved in cellular processes, from higher order assembly to protein degradation. Even though HSF-1 transcripts are expressed in the majority of adult tissues under physiological growth conditions, the activity of HSF-1 protein is suppressed by phosphorylation. Despite the increasing evidence regarding the function of hsps, significantly less is known about the mechanisms controlling HSF-1 activity and its genomic organization. Our recent results reveal that the extracellular-signal regulated kinase (ERK1), glycogen synthase kinase (GSK-3beta) and c-Jun N-terminal kinase (JNK1) repress HSF-1 transcriptional activity after heat shock by facilitating the diffusion of HSF-1 molecules from the sites of transcription. In addition, investigation of the genomic organization of the murine HSF-1 gene indicate that HSF-1 has a bidirectional promoter that also drives the expression of the recently described Bop1 gene. In this proposal, we will further define the molecular control mechanisms involving phosphorylation-dependent HSF-1 nuclear import and export trafficking. We will attempt to understand how HSF-1 is regulated via its genomic organization and at the level of expression by the appearance of multiple isoforms. We will also explore the physiological function of HSF-1 in vivo by targeted disruption of the HSF-1 gene. This mouse model will be used to further elucidate the role of HSF-1 as a transcriptional regulator of heat shock proteins following stress.
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