REGULATION OF DIFFERENTIATION OF TRACHEOBRONCHIAL EPITHELIAL CELLS

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 和表皮角质形成细胞，特别是维甲酸所扮演的角色 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，细胞经历不可逆转的生长停滞。这种增长 停滞是鳞状细胞表型表达的必要条件 (第二阶段)。鳞状细胞分化的一个特征是 交联膜的形成，一层交联化的蛋白质 形成于质膜之下。两个基因，转谷氨酰胺酶I型和 科尼芬，其产品在形成这一过程中发挥了重要作用 信封已经被克隆了。Cornifin是一种新型的交联型包膜蛋白 它富含谷氨酰胺和脯氨酸。Cornifin成为交联物 转谷氨酰胺酶形成的高分子复合体。转谷氨酰胺酶基因 已经被克隆和测序。有几个地区监管 该基因的转录已在其启动子中被鉴定。这个 鳞状细胞特异性基因的表达被维甲酸抑制。 这一调节似乎发生在转录水平上，并且是 由核维甲酸受体介导。表皮角质形成细胞 表达核维甲酸受体RARAlpha、RARGamma和 RXRAlpha。这些基因表达的改变可能在 癌变致癌的过程许多肺鳞状细胞癌 在维甲酸诱导RARbeta的过程中似乎存在缺陷。 另一个例子是早幼粒细胞白血病，其易位涉及 转录因子PML和RARα在诱导过程中起作用 恶性表型。我们的实验室已经证明PML/RARAlpha 融合蛋白对维甲酸的亲和力与RARpha相似， 与RARpha一样，它主要定位于细胞核。PML/RARAlpha 融合蛋白与自身或其自身形成高分子量的复合体 其他核蛋白。后者可能在白血病的发生中起重要作用。

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.