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Transcriptional regulation by bhlh-pas proteins; a novel family of transcription factors


Regulation of gene expression under hypoxic conditions is an important feature of many medically very relevant processes. The hypoxia-inducible factor HIF-la mediates transcriptional responses to hypoxia by dimerizing with the transcription factor Arnt. Both HIF-la and Arnt are members of a novel subclass, bHLH-PAS, of the basic helix-loophelix (bHLH) family of transcription factors. Regulation of gene expression by HIF-1 will be examined in detail at two critical steps in the signal transduction cascade: ? Mechanism of conditional regulation of HIF-1, i.e. mechanism of repression and derepression. ? Identification and characterization of co-factors that mediate (or repress) transcriptional activation by HIF-1. Are these factors similar to or distinct from coactivators of members of the steroid hormone receptor superfamily? Is the functional communication with these factors by HIF- 1 regulated by hypoxia? More specifically, the domain of HIF mediating hypoxia responsiveness will be identified, and it will be examined if this domain represents a novel ligand binding domain for an as yet unknown class of compounds. Moreover, to understand the mechanism of HIF-1 signaling we will examine if HIF- 1, a putative orphan receptor, recruits a similar battery of transcrptional co-activators as steroid hormone receptors, and whether the already indentified factors, are, in fact, also facilitating transcriptional activation by conditionally regulated bHLH-PAS factors. If this is not the case, novel co-activators will be identified in parallel two-hybrid screens in yeast. The present program aims to investigate the molecular mechanism of conditional regulation of the HIF- I, a potential orphan receptor. These studies will be important for our understanding of the phyisological function of HIF and the mechanism of pathophysiology during hypoxia under a great number of medically very relevant conditions. Moreover, this study represent a critical step in the investigation of the biology of the novel class of bHLH/PAS factors, which, in addition to HIF and the dioxin receptor, includes a number of key developmental factors. The program combines the expertice of the applicant in steroid hormone receptor signaling with a laboratory with a proven track record in bHLH-PAS factor biology, and it is expected to generate results of high impact with regard to our understanding of the biology of this very interesting novel family of putative intracellular orphan receptors Lints with industry / industrial relevance (22)

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