REGULATION OF DIFFERENTIATION OF TRACHEOBRONCHIAL EPITHELIAL CELLS

我们的研究一直集中在调节 正常气管、支气管和表皮细胞的增殖和分化 上皮细胞为此目的，人的支气管和表皮，以及 兔气管上皮细胞用作体外模型系统。一 增生和鳞状化生的多阶段程序已经被 提出了转化生长因子β和类维生素A影响 这些细胞的增殖和分化。TGF-β 1和TGF-β 2 抑制细胞生长但不诱导鳞状分化。TGF-beta 治疗诱导了几种基因产物包括转氨酶II型， 纤连蛋白、胶原IV和层粘连蛋白。这一增长是在 蛋白质和mRNA水平。其中一些基因的调节是 依赖于蛋白质合成和分化的状态， 气管支气管上皮细胞分离了几个cDNA克隆， 编码在鳞状分化细胞中大量表达的mRNA， 在未分化细胞中以低浓度存在。这些cDNA 测序和从它们各自的DNA推导的氨基酸序列 顺序克隆SQ 37代表一个1.0 kb的mRNA，它编码一个 富含脯氨酸的蛋白质，含有八个氨基酸的串联重复序列。pTG-7 代表编码I型转氨酶的3.6kb mRNA。维甲酸 抑制SQ 37、I型转氨酶、外皮蛋白的表达， 其他鳞状细胞特异性mRNA。气管支气管和表皮 上皮细胞含有核视黄酸受体（RAR）活性。 这些细胞表达相对高水平的RAR α和RAR γ， RAR β水平。视黄酸处理增加RARb mRNA水平 气管支气管上皮细胞中有表达，而表皮细胞中无表达。我们建议这些RAR 介导维甲酸对气管支气管基因表达的作用 上皮细胞肺癌细胞显示异常表达 RAR β和RAR γ。RAR的表达缺陷可能在 在这些细胞中建立恶性表型。

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.