THE USE OF TRANSCRIPTIONAL FACTORS AS TARGETS AND AGENTS FOR CHEMOPREVENTION

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Transcriptional factors are critical regulators of gene expression. It is clear that these factors control the expression of many genes and as such mediate the biologic effects of agents such as "tumor promoters." The purpose of this project is to design mutants of transcription factors speci~cally aimed at inhibiting their biochemical and, most importantly their biologic functions. The AP-1 complex has been speci~cally implicated in mediating the biologic effects of the tumor promoters "phorbol esters." A major component of this complex is the c-jun oncogene. We have created a panel of dominant-negative mutants of c-jun which are able to inhibit the biochemical functions of this oncogene. These mutants include: 1) a transactivation mutant with a deletion of amino acids 2-122, 2) 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, 3) a dimerization dependent mutant missing the Leucine zipper, 4) a transactivation mutant (deletion of amino acids 2-122) with a homodimerization domain only, and 5) a transactivation mutant with a heterodimerization domain only. We have recently begun to test the ability of these mutants to inhibit biologic functions. A transactivation mutant has been shown to inhibit Jun and Fos oncogene transformation in addition to the in vitro transforming effects of the tumor promoter TPA. Further work with this mutant has demonstrated that it can inhibit a wide range of oncogene transformation, the effects of phorbol ester in in vivo model systems of "tumor promotion," and tumorgenicity of some mouse epidermal tumor cell lines. Future efforts are aimed at further re~ning the potency and speci~city of these mutants by creating smaller mutants with higher af~nities for dimerization and DNA binding, and testing them in speci~c human tumor systems such as breast and lung cancers. In addition, we are designing delivery mechanisms which might make these agents more clinically applicable. Finally, we are expanding these studies to include other transcription factors such as CREB.