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 molecular mechanisms that regulate the differentiation of tracheobronchial and epidermal epithelial cells and in particular the role that retinoids play in this process. Retinoids affect a specific stage in the multi-stage process of squamous differentiation. These agents do not block the commitment to irreversible growth arrest but specifically suppress the induction of squamous cell-specific genes. The formation of the crosslinked envelope, a layer of crosslinked protein deposited beneath the plasma membrane, is a characteristic feature of squamous differentiation. The promoter of the transglutaminase type I gene, the enzyme that catalyzes the protein crosslinking, has been cloned and sequenced. Different regions of the promoter of this gene were cloned into reporter gene constructs and transfected into cells in order to analyze what elements are important in the transcriptional control of this gene. Putative AP1 and AP2 sites were found to be important in the transcriptional control of this gene. The cDNA clone SQ37 was characterized and found to encode a new squamous cell- specific protein named cornifin. Immunohistochemistry and in situ hybridization localized the cornifin protein and mRNA in the suprabasal layers of several squamous differentiating tissues. Cornifin is a cytosolic protein that contains 13 repeats of an octapeptide (consensus sequence, EPCQPKVP) at the carboxy terminus and is high in the content of proline and glutamine. Cornfin is an excellent substrate for transglutaminase type I and appears to function as a precursor protein for the crosslinked envelope. Cornifin appears to be a gene family since other genes were cloned exhibiting high homology to cornifin. The suppression of transglutaminase type I by retinoic acid occurs at the transcriptional level and appears to be mediated through nuclear retinoic acid receptors. The suppression of cornifin expression by retinoic acid appears to occur at least in part at a post-transcriptional level. Retinoids selective for specific retinoid receptors are being used to determine which receptor is mediating the various effects of retinoids.