POCKET PROTEIN/E2F REGULATES LUNG CELL DIFFERENTIATION

口袋蛋白/E2F 调节肺细胞分化

• 批准号: 6242151
• 负责人: Jerome S Brody
• 金额: $ 31.65万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6242151
• 关键词: cell differentiation; cell line; developmental genetics; embryo /fetus tissue /cell culture; gene expression; genetic regulation; genetic transcription; genetically modified animals; laboratory mouse; lung alveolus; lysozyme; pulmonary surfactants; respiratory epithelium; retinoblastoma protein; transcription factor

This project has as its goal an exploration of the roles that the retinoblastoma family of proteins (pRb, p107, p130), the E2F family of proteins (E2F-1 to E2F-5) and the CBP/p300 proteins play in the regulation of alveolar epithelial cell differentiation. The pRb/E2F proteins have been intensively studied because of their critical role in cell cycle regulation. However, increasing evidence from a number of systems suggests that they also play important roles in cell differentiation. CBP/p300 have recently been described as co-activators of gene transcription and appear to serve as mediators of multisignal transduction pathways. Both pRb and CBP/p300 complex with a number of factors that have the potential to influence lung cell gene expression. These include for pRb, the glucocorticoid response element and the transcription factor C/EBP; for CPB/p300, the cAMP response element, AP-1 and a number of nuclear hormone receptors. The surfactant proteins, T1 alpha and GGT all contain putative binding sites for these elements. We therefore plan to: 1) define the timing and sites of expression of the pRb and E2F gene families in normal and pRb family null mutant mice; 2) examine the role that the E2F-5 gene we have cloned from the lung plays in regulating lung cell proliferation and differentiation; and 3) determine whether CBP/p300 plays an important role in regulating expression of lung epithelial cells. Preliminary studies provide data that supports the rationale for each of this aims. The studies will be carried out using cell lines, in vitro embryonic lung culture systems and transgenic mice. We will focus on how pRb affects expression of the lat alveolar genes, SP-A, SP-D and lysozyme and how CBP/p300 regulates expression of these and other genes being studied in the PPG. The studies we propose continue the goals set forth in the first five years of this Project, which were to explore the relationship between lung epithelial cell proliferation an differentiation, but focus our studies on specific mechanisms.

该项目的目标是探索 视网膜母细胞瘤蛋白家族（pRb，p107，p130），E2 F 蛋白质家族（E2 F-1至E2 F-5）和CBP/p300蛋白质 在调节肺泡上皮细胞分化中发挥作用。 pRb/E2 F蛋白已被深入研究，因为 它们在细胞周期调节中的关键作用。 然而，日益 许多系统的证据表明， 在细胞分化中的重要作用。 CBP/P300最近 被描述为基因转录的共激活因子， 作为多信号转导通路的介质。 两 pRb和CBP/p300复合物与许多因素， 影响肺细胞基因表达的潜力。 这些包括 对于pRb，糖皮质激素反应元件和转录， 因子C/EBP; CPB/p300，cAMP反应元件，AP-1 和一些核激素受体。 表面活性剂 蛋白质，T1 α和GGT都含有推定的结合位点， 这些元素。 因此，我们计划：1）确定时间， pRb和E2 F基因家族在正常人中的表达位点 和pRb家族无效突变小鼠; 2）检查 我们从肺中克隆的E2 F-5基因在调节肺功能中起着重要作用 细胞增殖和分化;以及3）确定是否 CBP/p300在肺组织中的表达调控中起重要作用 上皮细胞 初步研究提供的数据支持 每个目标的基本原理。 这些研究将在 使用细胞系、体外胚胎肺培养系统和 转基因小鼠我们将重点关注pRb如何影响 最新肺泡基因，SP-A，SP-D和溶菌酶，以及如何 CBP/p300调节这些和其他基因的表达， 研究了PPG。 我们建议的研究继续了既定的目标 在这个项目的前五年，我们将探索 肺上皮细胞增殖与 分化，但我们的研究集中在具体的机制。