ZEB/deltaEF1 and Estrogen Signaling Cascades

ZEB/deltaEF1 和雌激素信号级联

• 批准号: 6721290
• 负责人: MICHEL M SANDERS
• 金额: $ 24.26万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-14 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6721290
• 关键词: ZEB; deltaEF1; Estrogen; Signaling; Cascades

DESCRIPTION (provided by applicant): In addition to its normal physiological functions, estrogen directs events that lead to both the protection from and promotion of many pathological conditions. However, the molecular details linking the binding of the receptor to its target genes with the ultimate biological consequence often remain unclear. In an attempt to define signaling cascades triggered by estrogen, the novel observation was made that the ZEB/dEF1 gene is induced at the transcriptional level by estrogen. Other data show that ZEB/dEF1 is one of the links in estrogen signal transduction pathways in reproductive tissues. For example, ZEB/dEF1 expression is high in rapidly proliferating endometrial and ovarian cancers but is no longer regulated by estrogen. In contrast, the gene is deleted in slowly growing endometrial cancers. These data suggest that ZEB/deltaEF1 plays a pivotal role in reproductive tissues. ZEB/deltaEF1 is a transcription factor that contains several functional domains including two zinc finger clusters at each terminus. Most data suggest that ZEB/deltaEF1 is a transcriptional repressor but in some circumstances it functions as a transcriptional activator. The overall goals of this proposal are to define the mechanism of gene activation by ZEB/deltaEF1 and to identify its target genes. The specific aims of this proposal are to 1). Investigate the mechanism of gene activation by ZEB/deltaEF1, 2). Identify the proteins in reproductive tissues that act as co-activators with ZEBdeltaEF1, and 3). Identify the downstream targets of ZEB/deltaEF1 in a breast cancer cell line. The first aim will be approached primarily by truncating ZEB/dEF1 and determining the effects on reporter gene activation. The second specific aim will be addressed by two complementary approaches, tandem mass spectrometry and a yeast two-hybrid Ras recruitment system. For the last specific aim, target genes for ZEB/deltaEF1 will be identified using gene profiling with DNA microarrays. These experiments will provide important information about the mechanism of gene activation by ZEB/deltaEF1 and about estrogen signal transduction pathways.

描述（由申请人提供）：除了其正常的生理功能外，雌激素还指导事件，导致对许多病理状况的保护和促进。但是，将受体与其靶基因结合与最终生物学后果联系起来的分子细节通常尚不清楚。为了定义由雌激素触发的信号传导的级联反应，使新的观察结果表明Zeb/def1基因是通过雌激素在转录水平诱导的。其他数据表明，Zeb/def1是生殖组织中雌激素信号转导途径的联系之一。例如，Zeb/def1表达在快速增殖的子宫内膜和卵巢癌中很高，但不再受雌激素的调节。相比之下，该基因在缓慢生长的子宫内膜癌中被删除。这些数据表明Zeb/deltaef1在生殖组织中起关键作用。 Zeb/deltaef1是一个转录因子，其中包含几个功能域，包括每个末端的两个锌指簇。大多数数据表明Zeb/deltaef1是转录阻遏物，但在某些情况下，它可以充当转录激活器。该提案的总体目标是定义Zeb/deltaef1的基因激活机制，并确定其靶基因。该提案的具体目的是1）。研究Zeb/deltaef1，2）基因激活的机理。鉴定在生殖组织中充当与Zebdeltaef1共激活剂的蛋白质，而3）。在乳腺癌细胞系中确定Zeb/deltaef1的下游靶标。第一个目标将主要通过截断Zeb/def1并确定对报告基因激活的影响。第二个特定目的将通过两种互补方法，串联质谱和一个酵母双杂种RAS募集系统来解决。对于最后的特定目的，将使用带有DNA微阵列的基因分析来鉴定Zeb/deltaef1的靶基因。这些实验将提供有关Zeb/deltaef1和雌激素信号转导途径的基因激活机制的重要信息。