The human glucocorticid receptor, its gene and actions

超出所提供的空间。这项持续资助的长期目标是了解糖皮质激素受体（GR）如何调节基因以影响白血病淋巴细胞的死亡。我们的发现为我们下一个资助期的研究奠定了基础。糖皮质激素，通过激活GR，已经确定了几个里程碑式的基因，糖皮质激素的调节之前发生的明显的细胞凋亡。具有高度意义的是观察到c-myc的转录抑制总是在对糖皮质激素敏感的细胞中观察到（或通过蛋白激酶A的活化而变得敏感）。我们已经开始基因阵列分析，以揭示所有这些基因的最终凋亡事件。我们已经从人急性淋巴细胞白血病CEM细胞系中开发了一组控制良好的克隆细胞系。比较这些克隆中表达的基因将使我们能够鉴定其调节与凋亡发作特异相关的基因。我们最近发现的两种药物干预，增强糖皮质激素诱发的细胞凋亡，应该允许进一步完善这一基因集。基于这些发现，在下一个资助期内，我们的研究将集中在四个具体目标上。我们将：1）通过基因阵列分析确定糖皮质激素诱发的CEM细胞死亡所需的表达改变的那些基因; 2）测试这些基因之间的假设因果关系; 3）获得糖皮质激素敏感细胞特有的蛋白质表达谱;和4）测试GR的主要N-末端转录激活结构域在上述调节事件中的作用。为了进行这些实验，我们将结合联合收割机在分子和细胞生物学，基因组学，蛋白质组学和生物信息学的专业知识。由此产生的数据将测试的假设，一个网络的相互作用的基因产物是负责糖皮质激素诱发的细胞凋亡。如果我们的假设是正确的，这项工作将导致在白血病细胞系统中发现该网络，为与其他淋巴系统（正常和恶性）进行详细比较提供基础。这将为针对恶性肿瘤的新干预措施的研究开辟道路。性能现场=

EXCEED THE SPACE PROVIDED. The long-term goal of this ongoing grant is understanding how the glucocorticoid receptor (GR) regulates genes to effect the death of leukemic lymphoid cells. Our findings have laid the groundwork for research in our next grant period. Glucocorticoids, through activation of the GR, have identified several landmark genes whose regulation by glucocorticoids precedes the onset of overt apoptosis. Of high significance is the observation that transcriptional repression of c-myc is invariably seen in cells sensitive to glucocorticoid (or rendered sensitive by activation of protein kinase A). We have begun gene array analysis to reveal all such genes antecedent to the eventual apoptotic events. We have developed a well-controlled set of clonal cell lines from the human acute lymphoblastic leukemia CEM cell line. Comparing the genes expressed in these clones will allow us to identify the genes whose regulation is specifically relevant to apoptotic onset. Our recent discovery of two pharmacological interventions that enhance glucocorticoid-evoked apoptosis should allow further refinement of this gene set. Based on these findings, in the next grant period our research will center on four specific aims. We will: 1) define by gene array analysis those genes whose altered expression is required for glucocorticoid-evoked CEM cell death; 2) test the hypothetical causal relationships between such genes; 3) obtain protein expression profiles unique to glucocorticoid-sensitive cells; and 4) test the role of the major, N-terminal transcription-activating domain of the GR in the above regulatory events. To carry out these experiments, we will combine expertise in molecular and cell biology, genomics, proteomics and bioinformatics. The resulting data will test the hypothesis that a network of interactive gene products is responsible for the glucocorticoid-evoked apoptosis. If our hypothesis is correct, this work will lead to the discovery of that network in a leukemic cell system, providing the foundation for detailed comparisons with other lymphoid systems, normal and malignant. This would open the way for studies of novel interventions against malignancies. PERFORMANCE SITE ========================================Section End===========================================