VIMENTINSS REGULATORY FACTORS INVOLVED IN DEVELOPMENT

描述(改编自研究人员摘要)：肌肉发生需要 协调肌肉特有基因的表达和其他基因的失活， 这些都不是肌肉表型所必需的。虽然相当可观 关于控制骨骼基因和现在的心脏基因的信息已经存在 事实上，对于非肌肉特异性基因是如何表达的，我们几乎一无所知 在肌肉发生过程中被关闭，尽管事实上基因失活是 对保持肌肉表型同样重要。细胞骨架 蛋白质，波形蛋白和结蛋白，提供了一个很好的模型系统 确定基因在发育过程中的差异表达方式。波形图 合成首先在中胚层的描绘处被检测到。一批 细胞类型从这一谱系分化而来，并继续合成波形蛋白。 其他的，比如肌肉，会使波形蛋白基因失活，并“激活”结蛋白。这个 这项提议的目的是描绘波形蛋白基因是如何特异性地 肌肉发生过程中的失活以及这些调控基因的异常表达 调控因素可能会影响发育计划。显然，任何 这一决定的偏差可能会危及发展。在分析振动时 基因表达方面，研究人员发现了一种独特的阳性组合 以及负面监管因素，这些因素控制着对 波形蛋白基因。首先，基础基因和调控基因的表达都是绝对的 依赖于一个GC盒，它结合了调节因子Sp2。他们不知道没有 其他使用Sp2而不是Sp1/Sp3蛋白的基因。上游 调查人员已经找到了一个消音器元件，它绑定了锌手指 蛋白质，ZBP-。更上一层楼是一个积极的因素，它是 调查人员称其为反消音器，因为它只能与 消音器本身并不会促进基因的表达，这与 典型的增强剂。此前，研究人员曾在鸡的骨骼中显示 成肌细胞，沉默因子的结合活性低， 抗沉默剂含量高，波形蛋白基因表达丰富。随着肌肉发生的进行， 消音器因子的活性显著增加，而抗消音器 活动消失，Vimentin基因表达水平显著降低。 因此，这两个因素和Sp2的相互作用对 确定波形蛋白基因的生理正确表达。 由于心脏中消音器因子的活动更占优势，所以 研究人员得出结论，类似的程序肯定发生在心脏手术期间 肌肉发生。在这项提案中，研究人员的目标是确定这种机制 这些调节因子通过其相互作用和控制转录。与 获得cDNA后，研究人员计划改变细胞内的DNA含量 这些因素在正常细胞和肌肉细胞中都存在，并决定了由此产生的 对肌肉发生的影响。他们怀疑ZBP-89是一种肿瘤抑制因子。 因此，它的细胞含量的变化可能会影响细胞周期和 末端分化。他们将检查这些密钥的表达方式 胚胎发育过程中的调控因素。最后，调查人员将 继续我们对波形蛋白mRNA转录后调控的研究 本地化、稳定性和翻译性。希望通过一次彻底的 了解这些基因控制如何促进发育， 调查人员最终可以确定异常情况可能会如何发展 心。

DESCRIPTION (adapted from investigator's abstract): Myogenesis requires the coordinate expression of genes unique to muscle and the inactivation of others, which are not require for the muscle phenotype. Although considerable information exists about what controls skeletal and now cardiac gene expression, virtually nothing is known about how non-muscle-specific genes are "turned-off' during myogenesis, despite the fact that gene inactivation is equally important to maintaining the muscle phenotype. The cytoskeletal proteins, vimentin and desmin, provide an excellent model system for determining how genes are differentially expressed during development. Vimentin synthesis is first detected at the delineation of the mesoderm. A number of cell types differentiate from this lineage and continue to synthesize vimentin. Others, like muscle, inactivate the vimentin gene and "turn-on" desmin. The goal of this proposal is to delineate how the vimentin gene is specifically inactivated during myogenesis and how aberrant expression of these controlling regulatory factor could affect the developmental program. Obviously, any deviation in this decision could compromise development. In analyzing vimentin gene expression, the investigators have found a unique combination of positive and negative regulatory factors, which control the down-regulation of the vimentin gene. First, both basal and regulated gene expression is absolutely dependent on a GC box, which binds the regulatory factor, Sp2. They know of no other gene which uses Sp2 instead of Spl/Sp3 proteins. Upstream the investigators have located a silencer element, which binds the zinc finger protein, ZBP-89. Further upstrearn is a positive-acting element, which the investigators call an anti-silencer, because it only functions in concert with the silencer and does not contribute to gene expression on its own unlike the typical enhancer. Previously, the investigators have shown in chick skeletal myoblasts, that the binding activity of the silencer factor is low, the antisilencer is high, and vimentin mRNA is abundant. As myogenesis proceeds the activity of the silencer factor increases dramatically, whereas antisilencer activity disappears and the level of vimentin mRNA decreases dramatically. Therefore, the interplay of these two factors and Sp2 is crucial for determining the physiologically correct expression of the vimentin gene. Because silencer factor activity is more predominant in heart, the investigators conclude a similar program must be occurring during cardiac myogenesis. In this proposal the investigators aim to determine the mechanism by which these regulatory factors interact and control transcription. With the acquisition of cDNAs, the investigators plan to alter the cellular content of these factors in both normal and muscle cells and determine the resulting effect on myogenesis. They suspect that ZBP-89 is a tumor suppressor. Therefore, an alteration in its cellular content could affect cell cycle and terminal differentiation. They will examine the expression of these key regulatory factors during embryogenesis. Finally, the investigators will continue our investigation of post-transcriptional controls of vimentin mRNA localization, stability, and translation. It is hoped that by a thorough understanding of how these genetic controls contribute to development, the investigators can ultimately determine how abnormalities may develop in the heart.