The role and biology of Fra-1 in lung injury and repair

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Aberrant cell proliferation and differentiation following toxic injury to bronchial epithelium can lead to the development of various respiratory diseases including lung cancer, but the underlying molecular mechanisms involved in such processes remain enigmatic. The proposed research is based on the premise that AP-1 family of transcriptional factors act as environmental biosensors to various external toxic stimuli and regulate genes involved in cell proliferation and differentiation. Recently we have shown that Fra-1 (fos-related transcription factor-1), a member AP-1 family, up regulates the gene expression involved in airway squamous metaplasia, a preneoplastic lesion. Other studies have demonstrated a protracted expression of Fra-1 in response to silica and asbestos exposure, which causes bronchial epithelial cell transformation. Furthermore, we have observed that Fra-1 expression is induced by phorbol ester PMA and tobacco smoke in airway epithelial cells both in vitro and in vivo. Therefore, we hypothesize that protracted induction of Fra-1 expression by toxicants compromises the normal bronchial epithelial cell growth and differentiation thereby altering pulmonary defense and injury-repair processes, which culminate in cellular transformation. The proposed Specific Aims to test the above hypothesis are to: 1) Define the promoter cis-acting elements and trans-acting factors that regulate PMA and tobacco smoke-inducible Fra-1 expression by in vivo footprinting, deletion/mutation and electrophoretic mobility shift assays. 2) Elucidate the signal transduction pathways that mediate PMA- and tobacco smoke-inducible fra1 expression employing pharmacological inhibitors as well as genetic mutants of various mitogen-activated protein kinases; and 3) Examine the functional role of Fra-1 in PMA- and tobacco smoke-induced bronchial epithelial injury-repair and transformation. To achieve these objectives, we will use two independent, but complementary approaches that utilize in vitro cell culture and in vivo transgenic mouse models that over express wild type or dominant negative-mutant Fra-1, specifically in bronchial epithelial cells. These studies should provide additional insight into mechanisms of toxicant-inducible gene expression and also establish the specific role for Fra-1 in lung biology and toxicant-induced respiratory pathogenesis. Also, these results should enable us to identify lung-specific Fra-1-inducible genes that might offer unique opportunity to use them as potential diagnostic markers or drug targets for early detection and prevention of respiratory pathogenesis.