REGULATION OF DIFFERENTIATION OF TRACHEOBRONCHIAL EPITHELIAL CELLS

气管支气管上皮细胞分化的调控

• 批准号: 3841064
• 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/3841064
• 关键词: bronchus; cell differentiation; cell population study; cell transformation; chimeric proteins; gene expression; genetic promoter element; genetic regulation; genetic transcription; glutamine; human tissue; keratinocyte; leukemia; membrane proteins; membrane structure; messenger RNA; molecular cloning; nutrition related tag; proline; protein glutamine gamma glutamyltransferase; receptor; respiratory epithelium; retinoid binding proteins; retinoids; squamous cell carcinoma; tissue /cell culture; trachea; transforming growth factors

The focus of the research in the Cell Biology Section is to understand the molecular mechanisms that regulate the differentiation of tracheobronchial and epidermal keratinocytes and in particular the role that retinoids play in this process. Squamous cell differentiation is a multi-stage process. In the first stage, cells undergo irreversible growth arrest. This growth arrest is a requirement for the expression of the squamous cell phenotype (stage 2). A characteristic feature of squamous differentiation is the formation of the cross-linked envelope, a layer of cross-linked protein formed beneath the plasma membrane. Two genes, transglutaminase type I and cornifin, whose products play an important role in the formation of this envelope have been cloned. Cornifin is a new cross-linked envelope protein that is high in glutamine and proline. Cornifin becomes cross-linked into high molecular complexes by transglutaminase. The transglutaminase gene has been cloned and sequenced. Several regions that regulate the transcription of this gene have been identified in its promoter. The expression of squamous cell-specific genes is suppressed by retinoids. This regulation appears to occur at the transcriptional level and be mediated by nuclear retinoic acid receptors. Epidermal keratinocytes express the nuclear retinoic acid receptors RARalpha, RARgamma, and RXRalpha. Alterations in the expression of these genes may play a role in the process of carcinogenesis. Many squamous cell carcinomas of the lung appear to be defective in the induction of RARbeta by retinoic acid. Another example is promyelocytic leukemia where a translocation involving the transcriptional factor PML and RARalpha plays a role in the induction of the malignant phenotype. Our laboratory has shown that the PML/RARalpha fusionprotein has a similar affinity for retinoids as RARalpha and that it, like RARalpha, is largely localized in the nucleus. The PML/RARalpha fusionprotein forms high molecular weight complexes with either itself or other nuclear proteins. The latter may be important to leukemogenesis.

细胞生物学部分的研究重点是了解细胞的生物学特性。 调节气管支气管分化的分子机制 和表皮角质形成细胞，特别是类维生素A 在这个过程中。 鳞状细胞分化是一个多阶段的过程。 在第一阶段，细胞经历不可逆的生长停滞。 这种增长 抑制是鳞状细胞表型表达的必要条件 （阶段2）。 鳞状细胞分化的一个特征是 形成交联的包膜，一层交联的蛋白质 形成于质膜之下。 两个基因，转氨酶I型和 cornifin，其产品在形成这种 信封被克隆了。 Cornifin是一种新的交联包膜蛋白 富含谷氨酰胺和脯氨酸 Cornifin交联成 高分子复合物。 转氨酶基因 已被克隆并测序 几个地区监管 该基因的转录已在其启动子中得到鉴定。 的 鳞状细胞特异性基因的表达被类视色素抑制。 这种调节似乎发生在转录水平， 由核视黄酸受体介导。 表皮角质形成细胞 表达核视黄酸受体RAR α、RAR γ，和 RXR α 这些基因表达的改变可能在 致癌的过程 许多肺鳞状细胞癌 似乎在视黄酸诱导RAR β方面存在缺陷。 另一个例子是早幼粒细胞白血病，其中易位涉及 转录因子PML和RAR α在诱导中起作用 恶性表型。 我们的实验室已经表明PML/RAR α 融合蛋白对类维生素A具有与RAR α相似的亲和力， 像RAR α一样，主要位于细胞核中。 PML/RAR α 融合蛋白与其自身或 其他核蛋白 后者可能是重要的白血病发生。