REGULATION OF DIFFERENTIATION OF TRACHEOBRONCHIAL EPITHELIAL CELLS

气管支气管上皮细胞分化的调控

• 批准号: 3876899
• 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/3876899
• 关键词: bronchus; cell cycle; cell differentiation; cell growth regulation; cell population study; cell transformation; cell type; epidermal growth factor; gene expression; genetic regulation; growth media; insulin; keratin; laboratory rabbit; messenger RNA; protein glutamine gamma glutamyltransferase; receptor; respiratory epithelium; retinoate; retinoid binding proteins; tissue /cell culture; trachea; transforming growth factors

Our studies have been focussing on the mechanisms that regulate the proliferation and differentiation in normal tracheobronchial and epidermal epithelial cells. For this purpose human bronchial and epidermal, and rabbit tracheal epithelial cells are used as in vitro model systems. A multi-stage program of hyperplasia and squamous metaplasia has been proposed. Transforming growth factor beta and retinoids influence the proliferation and differentiation of these cells. TGF-beta1 and TGF-beta2 inhibit cell growth but do not induce squamous differentiation. TGF-beta treatment induces several gene products including transglutaminase type II, fibronectin, collagen IV and laminin. This increase is observed at the protein as well as the mRNA level. The regulation of some of these genes is dependent on protein synthesis and the state of differentiation of the tracheobronchial epithelial cell. Several cDNA clones were isolated that encode mRNAs abundantly expressed in squamous differentiated cells and present at low abundancy in undifferentiated cells. These cDNAs have been sequenced and amino acid sequence deduced from their respective DNA sequence. The clone SQ37 represents a 1.0 kb mRNA which encodes a proline-rich protein containing a tandem repeat of eight amino acids. pTG-7 represents a 3.6 kb mRNA encoding transglutaminase type I. Retinoic acid suppresses the expression of SQ37, transglutaminase type I, involucrin and several other squamous cell-specific mRNAs. Tracheobronchial and epidermal epithelial cells contain nuclear retinoic acid receptor (RAR) activity. These cells express relatively high levels of RARalpha and RARgamma and low levels of RARbeta. Retinoic acid treatment increases the level of RARb mRNA in tracheobronchial but not in epidermal cells. We propose that these RARs mediate the action of retinoids on gene expression in tracheobronchial epithelial cells. Lung carcinoma cells show an aberrant expression of RARbeta and RARgamma. A defective expression of RARs may play a role in establishing a malignant phenotype in these cells.

我们的研究重点是调节机制 正常气管支气管和表皮的增殖和分化 上皮细胞。为此目的，人类支气管和表皮，以及 兔气管上皮细胞用作体外模型系统。一个 增生和鳞状化生的多阶段程序已被 建议的。转化生长因子β和类维生素A影响 这些细胞的增殖和分化。 TGF-β1 和 TGF-β2 抑制细胞生长但不诱导鳞状细胞分化。转化生长因子-β 治疗诱导多种基因产物，包括 II 型转谷氨酰胺酶， 纤连蛋白、IV 型胶原蛋白和层粘连蛋白。这种增加是在 蛋白质以及 mRNA 水平。其中一些基因的调节是 取决于蛋白质合成和分化状态 气管支气管上皮细胞。分离出几个 cDNA 克隆 编码在鳞状分化细胞中大量表达的 mRNA 未分化细胞中的丰度较低。这些 cDNA 已被 测序和从各自的 DNA 推导出的氨基酸序列 顺序。克隆 SQ37 代表一个 1.0 kb 的 mRNA，编码 富含脯氨酸的蛋白质，含有八个氨基酸的串联重复。 pTG-7 代表编码 I 型转谷氨酰胺酶的 3.6 kb mRNA。 视黄酸 抑制 SQ37、I 型转谷氨酰胺酶、外皮蛋白和 其他几种鳞状细胞特异性 mRNA。气管、支气管和表皮 上皮细胞含有核视黄酸受体（RAR）活性。 这些细胞表达相对较高水平的 RARalpha 和 RARgamma，并且表达较低水平的 RARalpha 和 RARgamma。 RARbeta 水平。视黄酸治疗可增加 RARb mRNA 水平 存在于气管支气管中，但不在表皮细胞中。我们建议这些 RAR 介导类维生素A对气管支气管基因表达的作用 上皮细胞。肺癌细胞异常表达 RARbeta 和 RARgamma。 RAR 的表达缺陷可能在 在这些细胞中建立恶性表型。