Super-activity of gene regulators in fibrosarcoma

描述(由申请人提供)：在人类肉瘤的小鼠模型中，细胞内受体(IR)活性在最终过渡到肿瘤细胞时显著增加。尽管受体功能的改变不太可能是癌症的原因，但它们可能是“被动的旁观者”，是细胞变化的标志，可能影响受体的“超激活”和癌症的进展。在这项研究中，我们将集中在代表侵袭性纤维瘤病(肿瘤前的最后一个阶段)和纤维肉瘤肿瘤的细胞系中糖皮质激素受体(GR)活性的变化模式。GR与特定的基因组糖皮质激素反应元件结合，并触发多组分、反应元件特异性调节复合体的组装。我们将定义GR上功能表面的模式，寻找与超激活相关的模式。此外，我们还将确定GRE序列、GR-DNA亲和力和GR-辅活化子在超激活基因中的招募之间的关系。这些研究将有助于更好地理解癌症作为一种调控过渡，以及细胞调控途径的结构、机制和选择性。

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.