LAMININ GENE EXPRESSION IN GLOMERULAR CELLS

肾小球细胞中的层粘连蛋白基因表达

• 批准号: 7921107
• 负责人: KAROL BOMSZTYK
• 金额: $ 9.59万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921107
• 关键词: Address; Be++ element; Beryllium; Binding; Binding Sites; CREB-binding protein; Cells; Complex; DNA; Development; EP300 gene; Elements; Enhancers; Extracellular Matrix; Gene Expression; Genes; Genetic Transcription; Glomerular Mesangial Cell; Goals; Growth Factor; HMGA1a Protein; Human; Kidney Diseases; Laminin; Mediating; Messenger RNA; Modeling; Molecular; Phosphorylation; Play; Property; Proteins; RNA Polymerase II; Renal glomerular disease; Research Personnel; Rodent; Role; Series; Signal Pathway; Signal Transduction; Smad Proteins; Smad protein; Testing; Transcription Coactivator; Transcriptional Activation; Transforming Growth Factors; Work; activating transcription factor; base; dC-Stretch-Binding Protein; design; glomerular basement membrane; glomerulosclerosis; human CREBBP protein; insight; mesangial cell; overexpression; programs; promoter; protein K; response; synergism; transcription factor

Glomerulosclerosis is the most serious sequela of progressive renal disease. Glomerulosclerosis results from an abnormal accumulation of proteins, some of which, that normal]y make up the glomerular basement membrane (GBM) and mesangial matrix (MM). Laminin is one of the components of GBM and MM that accumulates within glomeruti during the progression of glomerular disease. A number of growth factors including transforming growth factor-[_ (TGF-_), activate glomerular cells resulting in abnormal accumulation of laminin. Although laminin is known to play a key role in the development of glomerulosclerosis, the mechanisms that regulate expression of laminin chains are incompletely understood. Treatment of glomerular cells with TGF-[3 and other growth factors increases mRNA levels of laminin 71 chain. The human and rodent larrdnin y1 chain (LAMCt) gene promoters contain the critical ben-1 element that is activated by transcription factor #E3 (TFE3). In glomerular mesangial cells, the TFE3-mediated activation of the bcn-1 element is greatly augmented by Smad proteins, acting through the LAMC1 promoter's Smad- binding elements (SBE), and by the TGF-[3-signaling pathways. The bcn-l-element-dependent activation of the LAMC1 promoter by the synergistic action of TFE3 and Smad proteins provides insight into how TGF-_ mediates activation of the endogenous LAMC1 gene in these cells Expression of the transcriptional co-activator, CREB- binding protein (CBP), increased the activity of the LAMC1 promoter in mesangial cells. The goal of the current proposal is to define the molecular mechanisms responsible for the TFE3- and Smad-dependent activation of LAMC 1 gene transcription that is induced by TGF-[3 in glomerular cells. The following specific aims are proposed to explore these mechanisms. We will define the role of CBP and other co-activators in mediating the TFE3-Smad-dependent TGF-_-induced LAMC1 gene expression. We will identify components of the basal transcriptional machinery that interact with TFE3 protein and define their role in mediating TGF-fl-induced gene expression. We will define the molecular mechanisms responsible for the TFE3-Smad3 synergistic activation of the LAMC1 gene in response to TGF-_. These studies will provide insight into transcriptional mechanisms utilized by TGF-[_ to direct TFE3- and Smad- dependent LAMC1 gene transcription in glomerular cells. The results of these studies are anticipated to have a broad impact on understanding the basic mechanisms by which TGF-[3 triggers transcription of genes encoding components of extracellular matrix and of other genes expressed in glomerular cells.

肾小球硬化是进行性肾脏疾病最严重的后遗症。肾小球硬化症是由 蛋白质异常积累，其中一些蛋白质通常构成肾小球基底膜 (GBM) 和系膜基质（MM）。层粘连蛋白是 GBM 和 MM 的成分之一，在肾小球内积累 在肾小球疾病的进展过程中。多种生长因子，包括转化生长因子-[_ (TGF-_)，激活肾小球细胞，导致层粘连蛋白异常积累。尽管已知层粘连蛋白具有 在肾小球硬化的发展中起关键作用，调节层粘连蛋白链表达的机制是 不完全理解。用 TGF-[3 和其他生长因子治疗肾小球细胞会增加 mRNA 水平 层粘连蛋白 71 链。人类和啮齿动物 larrdnin y1 链 (LAMCt) 基因启动子包含关键的 ben-1 由转录因子#E3 (TFE3) 激活的元件。在肾小球系膜细胞中，TFE3 介导的 Smad 蛋白通过 LAMC1 启动子的 Smad 作用，大大增强了 bcn-1 元件的激活 结合元件 (SBE)，并通过 TGF-[3-信号通路。 bcn-l 元素依赖性激活 LAMC1 启动子通过 TFE3 和 Smad 蛋白的协同作用提供了对 TGF-_ 如何介导的深入了解 这些细胞中内源性 LAMC1 基因的激活 转录辅激活因子 CREB- 的表达 结合蛋白（CBP），增加系膜细胞中 LAMC1 启动子的活性。当前的目标 提议是定义负责 TFE3 和 Smad 依赖性 LAMC 1 激活的分子机制 肾小球细胞中由 TGF-[3 诱导的基因转录。建议探索以下具体目标 这些机制。 我们将定义 CBP 和其他共激活剂在介导 TFE3-Smad 依赖性 TGF-_ 诱导的过程中的作用 LAMC1 基因表达。 我们将鉴定与 TFE3 蛋白相互作用的基础转录机制的组件，并定义 它们在介导 TGF-fl 诱导的基因表达中的作用。 我们将定义 TFE3-Smad3 协同激活 LAMC1 的分子机制 响应 TGF-_ 的基因。 这些研究将深入了解 TGF-[_ 指导 TFE3- 和 Smad- 所利用的转录机制 肾小球细胞中依赖的 LAMC1 基因转录。这些研究的结果预计将具有广泛的 对理解 TGF-[3 触发编码成分基因转录的基本机制的影响 细胞外基质和肾小球细胞中表达的其他基因的。