REGULATION OF DIFFERENTIATION OF TRACHEOBRONCHIAL EPITHELIAL CELLS

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The focus of the research in the Cell Biology Section is to understand the mechanisms that regulate the differentiation of tracheobronchial and epidermal epithelial cells and in particular the role that retinoids play in this process. Several factors, including phorbol esters and interferon gamma (IF-gamma) have been identified that control irreversible growth arrest, the first stage in the process o squamous differentiation. In the next stage, a variety of biological, biochemical and molecular changes are induced which determine the squamous-differentiated phenotype. Several squamous cell-specific mRNAs were identified, cloned and sequenced. These include transglutaminase type 1, relaxin and several genes with unknown function, such as SQ37 and CL20. SQ37 appeared to belong to family of at least four highly homologous genes which encode proteins containing 7-12 repeats of eight amino acids. These proteins may fulfill a structural role in the cell. The induction of the squamous phenotype by IF-gamma is antagonized by transforming growth factor beta suggesting an interaction between their signal transduction pathways. Retinoids are important regulators of differentiation of these cells in vivo as well in vitro. Retinoids determine whether tracheobronchial epithelial cells undergo squamous or mucociliary differentiation. The induction of the squamous markers is suppressed by retinoids at the protein as well as mRNA level. The action of retinoids appears to be mediated by the nuclear retinoic acid receptors RAR-alpha, RAR-beta and RAR-gamma. It was proposed that the expression of RARO is a prerequisite for the induction of mucociliary differentiation. Altered expression of RARs may play a role in the process of carcinogenesis in the lung.