Mechanism of repression of squamous differentiation marker, SPRR1B, in malignant bronchial epithelial cells: role of critical TRE-sites and its transacting factors

The overexpression of SPRR1B in bronchial epithelium is a marker for early metaplastic changes and the loss of its expression is associated with an ir reversible malignant transformation. In the present study, we have used a m odel system consisting of normal and malignant bronchial epithelial (BE) ce lls to elucidate the differential transcriptional control of SPRR1B, SPRR1B expression is either detectable or PMA (phorbol 13-myristate 12-acetate) i ncluding squamous, adeno, small and large cell carcinomas. Loss of SPRR1B e xpression is correlated well with the lack of strong in vivo protein-DNA in teractions at the -152 bp promoter, which contains two functional TRE sites . Even though the basal level AP-1 protein DNA binding pattern is different between normal and malignant cells, PMA significantly enhances Jun and Fos binding to the consensus TRE site in both cell types. Intriguingly, the co mposition of AP-1 protein binding to the -152 to -86 bp SPRR1B promoter is quite different. In untreated cells, SPRR1B promoter is predominantly occup ied by JunD and Fra2, PMA significantly induced binding of JunB and Fra1 in normal cells, while JunB and Fra2 bound to TREs in the malignant cells. Ov erexpression of fr nl in malignant cells significantly enhanced SPRRIB prom oter activity. In contrast, overexpression of fra2, but not fra1, strongly reduced both basal and PMA-inducible promoter activities in normal cells. T ogether, these results indicate that either temporal expression and/or diff erential activation of AP-1 proteins, especially Fra1 and Fra2, might contr ibute to the dysregulation of terminal differentiation marker, SPRR1B, expr ession in various BE cells.