CREB in Differentiation of Bronchial Mucous Cells

CREB在支气管粘液细胞分化中的作用

• 批准号: 6910759
• 负责人: JA SEOK KOO
• 金额: $ 33.98万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6910759
• 关键词: biological signal transduction; bronchial mucus; cAMP response element binding protein; cell differentiation; cell growth regulation; cell line; clinical research; gene expression; gene induction /repression; human tissue; hyperplasia; inflammation; metaplasia; neoplastic cell; pathologic process; posttranslational modifications; prostaglandin E; protein structure function; respiratory epithelium; retinoate; secretion; tissue /cell culture

DESCRIPTION (provided by applicant): Despite recent advances in understanding of molecular signaling involved in airway mucin gene expression, mechanisms of hyperplastic/metaplastic mucous transformation of bronchial epithelial cells are still poorly understood. Our previous studies have demonstrated that retinoic acid (RA) regulates phenotypical expression of human bronchial epithelial cells in culture. RA induced mucin gene expression and normal mucous cell differentiation, while IRA deficiency caused a squamous metaplasia. Interestingly, RA increased the activity of the MUCSAC promoter, which contains a cAMP response element-site. Recently, we found that the RA-deficient squamous metaplastic NHTBE cells contain little or no active cAMP-responsive element-binding protein (CREB). Surprisingly, we also found that RA activated CREB. We further found that the proinflammatory cytokine interleukin-1beta (IL-1beta) induced overexpression of the MUCSAC gene in the mucous NHTBE cells, but did not in the squamous metaplastic NHTBE cells, and at the same time activated CREB in the mucous, but not the squamous cells. On the basis of these results, we hypothesize CREB is a key molecule controlling differentiation of airway epithelial cells under normal and diseased conditions. Activation of CREB by RA is a prerequisite for basal MUC5AC expression and normal mucous differentiation, and chronic, persistent overexpression and activation of CREB by specific inflammatory mediators plays a critical role in mucous cell hyperplasia and/or metaplasia and resultant mucus hypersecretion. This application will address this hypothesis by determining the molecular mechanisms whereby CREB regulates normal and aberrant bronchial epithelial cell differentiation.

描述（由申请人提供）：尽管最近在理解气道粘蛋白基因表达所涉及的分子信号传导方面取得了进展，但对支气管上皮细胞的增生/化生粘液转化的机制仍然知之甚少。我们之前的研究表明，视黄酸（RA）调节培养物中人支气管上皮细胞的表型表达。 RA 诱导粘蛋白基因表达和正常粘液细胞分化，而 IRA 缺陷则导致鳞状化生。有趣的是，RA 增加了 MUCSAC 启动子的活性，该启动子包含一个 cAMP 反应元件位点。最近，我们发现RA缺陷的鳞状化生NHTBE细胞几乎不含有或不含有活性cAMP反应元件结合蛋白（CREB）。令人惊讶的是，我们还发现RA激活了CREB。我们进一步发现促炎细胞因子白细胞介素-1β（IL-1β）在粘液NHTBE细胞中诱导MUCSAC基因过度表达，但在鳞状化生NHTBE细胞中则不然，同时激活粘液中CREB，但在鳞状化生NHTBE细胞中则不然。鳞状细胞。 基于这些结果，我们假设 CREB ​​是正常和患病条件下控制气道上皮细胞分化的关键分子。 RA激活CREB是基础MUC5AC表达和正常粘液分化的先决条件，并且特定炎症介质对CREB的慢性、持续过度表达和激活在粘液细胞增生和/或化生以及由此产生的粘液分泌过多中起着关键作用。本申请将通过确定 CREB ​​调节正常和异常支气管上皮细胞分化的分子机制来解决这一假设。