Super-activity of gene regulators in fibrosarcoma

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DESCRIPTION (provided by applicant): Intracellular receptor (IR) activities dramatically increase at the final transition to the tumor cell in the mouse model for human sarcoma. Although the changes in receptor function are not likely to be the cause of cancer, they may be "passive bystanders" that are markers of a cellular alteration that may effect both the "super-activation" of the receptors and the cancer progression. In this study, we will focus on the pattern of changes in activity of the glucocorticoid receptor (GR) in cell lines that represent aggressive fibromatosis (the last pre-tumor stage) and the fibrosarcoma tumor. GR binds to specific genomic glucocorticoid response elements and triggers assembly of multicomponent, response element-specific regulatory complexes. We will define patterns of functional surfaces on GR, seeking patterns that correlate with super-activation. In addition, we shall determine the relationship between GRE sequences, GR-DNA affinities, and GR- coactivator recruitment in super-activated genes. These studies will facilitate a better understanding of cancer as a regulatory transition, and of the structure, mechanism and selectivity of cellular regulatory pathways.