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The Use of Transcriptional Factors as Targets and Agents in Carcinogenesis

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Transcription factors are critical regulators of gene expression. It is clear that these factors control the expression of many genes and can mediate the effects of biologic agents such as "tumor promoters". The AP-1 complex has been specifically implicated in mediating the biologic effects of the tumor promoters "phorbol esters" A major component of this complex is the c-jun oncogene. The purpose of this project is to defined the role of c-jun in human carcinogenesis and to design mutants of transcription factors which can inhibit their biochemical and most importantly their biologic functions. Firstly, we are conducting a series of experiments to examine the effects of c-jun overexpression on cancer cells. We have defined the N-terminus of c-jun as important in its biochemical and biologic functions in rat fibroblast transformation assays. In addition, we are overexpressing c-jun in a variety of human epithelial cancer cell lines to ascertain the biologic effects of c-jun in these cells. Overexpression of c-jun in human breast cancer cells results in increased tumorgenicity and loss of hormonal regulation. Present experiments are examining the role of AP-1 in DNA repair and cis-platinin sensitivity in ovarian cancer We have created and tested a series of dominant-negative mutants of c-jun which are able to inhibit the biochemical functions of this oncogene. A transactivation mutant with a deletion of the N-terminal amino acids 2-122 has been shown to inhibit AP-1 transactivation and c-jun induced transformation. In addition, this mutant has been shown to inhibit cellular transformation by a wide range of oncogenes including c-fos, c-raf, ras, mos, and myc. Further, stable expression of this mutant protein in mouse epidermal cells can block phorbol ester induced tumor promotion. Our most recent efforts are aimed at furthering refining the potency and specificity of these mutants by creating smaller mutants with higher affinities for dimerization and DNA binding. These mutants will be tested in specific human tumor systems such as breast and lung cancers. We have now created a series of c-jun mutants containing larger N-terminus deletions producing small peptides containing only the leucine zipper (dimerization domain). In addition, three DNA binding mutants including one with a point mutation at position 265, a deletion at positions 269-272, and one with an insertion of 3 amino acids at position 265 have been produced. All of these mutants have been demonstrated to have a dominant-negative phenotype. Further, we have packaged a c-jun dominant negative mutant in an adenovirus vector. This virus can deliver high level expression of this mutant into a wide variety of cell types. We are presently testing the effects of this virus on biologic parameters such as proliferation, apoptosis, differentiation in cell types such as breast, lung, and ovarian cancers. Future efforts include in vivo testing in model systems. This will include analysis of the ability of these agents to suppress tumorgenicity in nude mice,in initiator-promoter skin carcinogensis models, in a zebrafish model, and in a metastasis mouse model.

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