ANGIOTENSIN REGULATION OF GENE EXPRESSION

描述：(改编自应用)慢性刺激血管紧张素II 受体影响细胞的增殖、生长和存活 心血管、神经、内分泌和肾脏组织。分子 血管紧张素转换酶II参与细胞生长的遗传编程机制 和扩散是未知的。他们的解释，对 了解AII在神经中的生理和病理生理学作用， 内分泌和心血管系统，是这项提案的中心目标。 首席研究员(PI)的研究揭示了一种新的信号 激活细胞生长和增殖的神经、神经胶质和 平滑的肌肉谱系。这一途径是通过诱导一种 成纤维细胞生长因子-2和成纤维细胞生长因子受体-1基因与 随后成纤维细胞生长因子-2和成纤维细胞生长因子受体-1蛋白直接积聚到细胞内 原子核。核成纤维细胞生长因子-2和成纤维细胞生长因子受体-1通过前馈机制激活 转录其他基因并诱导细胞生长和进入细胞 周而复始。PI表明，这种新的内核成纤维细胞生长因子-2/FGFR-1 肾上腺髓质细胞中的血管紧张素II受体激活通路， 星形胶质细胞和平滑肌细胞。分子机制，通过它 血管紧张素Ⅱ激活成纤维细胞生长因子-2-成纤维细胞生长因子受体-1通路的起始步骤是血管紧张素转换酶的研究重点 这项提议。等电点表明Ang II通过激活成纤维细胞生长因子-2基因 诱导具有血管紧张素Ⅱ反应区(AngⅡ)的多蛋白复合体 也介导成纤维细胞生长因子-2基因启动子的IIRR，-555/-512个碱基 由可溶性细胞因子激活，减少细胞接触。Ang IIRR是 与cAMP/PKC反应序列(-625/-556bp)分离，包含唯一的 蛋白质结合序列，并与新的转录因子相互作用。 PI的发现还表明，成纤维细胞生长因子-2和FGFR-1蛋白 在细胞核内蓄积，刺激血管紧张素Ⅱ受体相关 反式激活复合体，从而增强血管紧张素Ⅱ的激活 成纤维细胞生长因子-2基因。因此，基于所有这些信息，这一行动的中心目标是 项目是通过Ang II确定核转导机制 激活成纤维细胞生长因子-2基因和介导这一过程的血管紧张素Ⅱ受体 激活。作为模型，PI将使用培养的、未转化的牛 肾上腺髓质细胞(BAMC)。目标如下：1)识别 并克隆形成多种蛋白质的肾上腺髓质反式作用因子 血管紧张素Ⅱ受体的复合体及AT2和AT1在激活中的作用 2)进一步确定Ang IIRR的结构 复合体及其克隆蛋白组分的功能，以及3) 确定核内成纤维细胞生长因子-2和成纤维细胞生长因子受体-1蛋白在血管紧张素转换酶II激活中的作用 成纤维细胞生长因子-2启动子和血管紧张素Ⅱ受体复合体。

DESCRIPTION: (Adapted from the application) Chronic stimulation of Ang II receptors effects proliferation, growth and survival of cells in cardiovascular, neural, endocrine and kidney tissues. The molecular mechanism by which Ang II accesses genetic programming for the cell growth and proliferation are unknown. Their elucidation, essential for understanding physiological and pathophysiological effects of AII in neural, endocrine and cardiovascular system, is the central goal of this proposal. The principal investigator (PI's) studies have revealed a new signaling mechanism that activates cell growth and proliferation of neural, glial and smooth muscle lineages. This pathway is initiated by an induction of fibroblast growth factors (FGF-2) and FGF receptor-1 (FGFR-1) genes with the consequent accumulation of FGF-2 and FGFR-1 proteins directly into the cell nucleus. Nuclear FGF-2 and FGFR-1 activate through a feed-forward mechanism transcription of other genes and induce cell growth and entry into the cell cycle. The PI has shown that this new intracrine-nuclear FGF-2/FGFR-1 pathway is activated by Ang II receptor in adrenal medullary cells, astrocytes and smooth muscle cells. The molecular mechanisms through which Ang II activates the initial steps in FGF-2-FGFR-1 pathway is the focus of this proposal. The PI indicates that Ang II activates FGF-2 gene by inducing a multiple-protein complex with an Ang II responsive region (Ang IIRR, -555/-512 BP) of FGF-2 promotor that also mediates FGF-2 gene activation by soluble cytokines and reduced cell contact. Ang IIRR is separate from cAMP/PKC responsive sequences (-625/-556 BP), contains unique protein-binding sequences and interacts with new transcriptional factors. The PI's findings also indicate that the FGF-2 and FGFR-1 proteins accumulating in the cell nucleus, stimulate the Ang IIRR-associated transactivating complex and thereby serve to enhance Ang II activation of FGF-2 gene. Thus, based on all of this information, the central aim of this project is to identify nuclear transduction mechanism through with Ang II activates the FGF-2 gene and the type of Ang II receptors that mediate this activation. As a model, the PI will use cultured, non-transformed bovine adrenal medullary cells (BAMC). The aims are as follows: 1) To identify and clone adrenal medullary trans-acting factors that form multiple protein complex with Ang IIRR and to determine the role of AT2 and AT1 in activation of FGF-2 gene promotor, 2)To further determine the structure of Ang IIRR complex and the functions of its cloned protein components, and 3) To determine the role of nuclear FGF-2 and FGFR-1 proteins in Ang II activation of FGF-2 promotor and of Ang IIRR complex.