REGULATION OF DIFFERENTIATION OF TRACHEOBRONCHIAL EPITHELIAL CELLS

气管支气管上皮细胞分化的调控

• 批准号: 3755414
• 负责人: A M JETTEN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3755414
• 关键词: apoptosis; biological signal transduction; cell differentiation; crosslink; enzyme induction /repression; enzyme substrate; gene expression; genetic regulatory element; genetic transcription; molecular cloning; mutant; nucleic acid sequence; posttranscriptional RNA processing; protein glutamine gamma glutamyltransferase; respiratory epithelium; retinoid binding proteins; retinoids; skin; tissue /cell culture

The focus of the research in the Cell Biology Section is to understand the molecular mechanisms that regulate the differentiation of tracheobronchial and epidermal epithelial cells and in particular the role that retinoids play in this process. Retinoids affect a specific stage in the multi-stage process of squamous differentiation. These agents do not block the commitment to irreversible growth arrest but specifically suppress the induction of squamous cell-specific genes. The formation of the crosslinked envelope, a layer of crosslinked protein deposited beneath the plasma membrane, is a characteristic feature of squamous differentiation. The promoter of the transglutaminase type I gene, the enzyme that catalyzes the protein crosslinking, has been cloned and sequenced. Different regions of the promoter of this gene were cloned into reporter gene constructs and transfected into cells in order to analyze what elements are important in the transcriptional control of this gene. Putative AP1 and AP2 sites were found to be important in the transcriptional control of this gene. The cDNA clone SQ37 was characterized and found to encode a new squamous cell- specific protein named cornifin. Immunohistochemistry and in situ hybridization localized the cornifin protein and mRNA in the suprabasal layers of several squamous differentiating tissues. Cornifin is a cytosolic protein that contains 13 repeats of an octapeptide (consensus sequence, EPCQPKVP) at the carboxy terminus and is high in the content of proline and glutamine. Cornfin is an excellent substrate for transglutaminase type I and appears to function as a precursor protein for the crosslinked envelope. Cornifin appears to be a gene family since other genes were cloned exhibiting high homology to cornifin. The suppression of transglutaminase type I by retinoic acid occurs at the transcriptional level and appears to be mediated through nuclear retinoic acid receptors. The suppression of cornifin expression by retinoic acid appears to occur at least in part at a post-transcriptional level. Retinoids selective for specific retinoid receptors are being used to determine which receptor is mediating the various effects of retinoids.

细胞生物学部分的研究重点是了解 调控气管、支气管壁分化的分子机制 和表皮上皮细胞，特别是维甲酸的作用 在这个过程中发挥作用。维甲酸影响多个阶段中的特定阶段 鳞状细胞分化过程。这些代理不会阻止 承诺不可逆转的增长停滞，但明确抑制 鳞状细胞特异性基因的诱导。新世纪的形成 交联膜，一层沉积在膜下的交联蛋白 质膜，是鳞状细胞分化的特征。 转谷氨酰胺酶I型基因的启动子，该酶催化 蛋白质的交联性，已被克隆和测序。不同地区 将该基因的启动子克隆到报告基因构建体中 将其导入细胞，以分析哪些元素在 这种基因的转录控制。推测的AP1和AP2位点是 被发现在该基因的转录控制中起重要作用。这个 经鉴定，克隆SQ37编码一种新的鳞状细胞-- 一种名为角蛋白的特定蛋白质。免疫组织化学与原位 杂交法定位基底上角蛋白和信使核糖核酸 几层鳞状分化组织。科尼芬是一种 含有一个八肽的13个重复序列的胞浆蛋白(共识 序列，EPCQPKVP)位于羧基末端，其含量很高 脯氨酸和谷氨酰胺。玉米翅是一种很好的底物 转谷氨酰胺酶I型，似乎是一种前体蛋白 交联型信封。Cornifin似乎是一个基因家族，因为其他 克隆的基因与Cornifin高度同源。对中国的压制 转谷氨酰胺酶I型由维甲酸发生在转录 水平，似乎是通过核维甲酸受体介导的。 视黄酸对角蛋白表达的抑制作用似乎发生在 至少部分是在转录后水平上。维甲酸选择性治疗 特定的维甲酸受体被用来确定哪种受体是 调节维甲酸的各种作用。