NUCLEAR MATRIX MEDIATED TRANSCRIPTIONAL CONTROL OF OSTEOBLAST GENE EXPRESSION

我们将讨论这样的假设，即核基质对 细胞生长和骨特异性基因表达的转录调控 在成骨细胞表型的进行性发展过程中， 核基质在骨细胞发育过程中受到调节。我们的 实验策略最初是描述核基质的特征 与启动子具有序列特异性相互作用的蛋白质 调控序列：1)细胞周期调控的组蛋白基因 仅在增殖的成骨细胞中表达；以及2)骨钙素基因 成熟成骨细胞的增殖后表达 细胞外基质矿化。这些基因的调控表达 然后将检查核基质蛋白与成骨细胞的关系。 肿瘤的分化及其相关的潜在分子机制 核基质介导的发育转录控制。我们会 研究核基质的发育反应性 TGFbeta、1，25(OH)2D3和地塞米松。 我们的“工作模型”是核基质支持成骨细胞 通过促进基因定位来促进增殖和分化 以及反式激活因子的浓度和定位。 核建筑的这些特点，连同结构 基于染色质结构和核小体的基因组特性 组织可以影响相关基因的转录控制 随着细胞的生长和增殖后的成熟分化 成骨细胞。在完整的成骨细胞中可能支持 在多个独立的顺势作用要素中的监管活动， 从而有助于对转录进行积极和消极的控制 通过发育过程中的一系列生理介质 和类固醇激素反应。 在实验上解决这一假说与中心 计划项目的主题，细胞结构的参与作为其 调节细胞进行性发育表达并受其调控 生长和骨细胞相关基因。

We will address the hypothesis that the nuclear matrix contributes to transcriptional control of cell growth and bone-specific gene expression during progressive development of the osteoblast phenotype and that the nuclear matrix is regulated developmentally in bone cells. Our experimental strategy is initially to characterize the nuclear matrix proteins that exhibit sequence-specific interactions with promoter regulatory sequences of: 1) the cell cycle regulated histone genes expressed only in proliferating osteoblasts; and 2) the osteocalcin gene expressed post-proliferatively in mature osteoblasts undergoing extracellular matrix mineralization. The regulated expression of these nuclear matrix proteins will then be examined in relation to osteoblast differentiation and potential molecular mechanisms associated with nuclear matrix-mediated developmental transcriptional control. We will investigate the developmental responsiveness of the nuclear matrix to TGFBeta, 1,25(OH)2D3 and dexamethasone. Our "working model" is that the nuclear matrix supports osteoblasts proliferation and differentiation by facilitating gene localization as well as the concentration and localization of transactivation factors. These features of nuclear architecture, together with structural properties of the genome, based on chromatin structure and nucleosome organization can influence transcriptional control of genes associated with cell growth and with the post-proliferative, mature differentiating osteoblast. In intact osteoblasts may support the integration of regulatory activities at multiple, independent cis-acting elements, thereby contributing to positive and negative control of transcription by a broad spectrum of physiological mediators that are developmentally and steroid hormone responsive. Experimentally addressing this hypothesis is consistent with the central theme of the Program Project, the involvement of cell structure as its regulates and is regulated by progressive development expression of cell growth and bone cell-related genes.