THE USE OF TRANSCRIPTIONAL FACTORS AS TARGETS AND AGENTS FOR CHEMOPREVENTION

转录因子是基因表达的关键调节因子。 是 这些因素控制着许多基因的表达， 介导诸如“肿瘤促进剂”的药剂的生物效应。" 本项目的目的是设计转录因子的突变体 特别是针对抑制他们的生化，最重要的是， 其生物功能。 AP-1复合物特别与 介导肿瘤促进剂佛波醇酯的生物学效应。" 该复合物的主要成分是c-jun癌基因。 我们创造了 一组c-jun的显性阴性突变体，其能够抑制 这种致癌基因的生化功能。 这些突变体包括： 第一章 具有氨基酸2-122缺失的反式激活突变体， （二） 三种DNA结合突变体，包括一种在 位置265处的缺失，位置269-272处的缺失，和具有插入的一个， 在位置265处的3个氨基酸， 3)缺失亮氨酸拉链的二聚化依赖性突变体， 四、 一种反式激活突变体（氨基酸2-122缺失）， 仅同二聚化结构域，和 第五章） 仅具有异源二聚化结构域的反式激活突变体。 我们最近开始测试这些突变体抑制 生物功能。 反式激活突变体已被证明可以抑制Jun Fos癌基因转化 肿瘤促进剂TPA的作用。 对这种突变体的进一步研究 证明它可以抑制广泛的癌基因转化， 佛波醇酯在“肿瘤促进”的体内模型系统中的作用， 和致瘤性。 今后的努力旨在进一步保持 这些突变体通过创造具有更高亲和力的较小突变体， 二聚化和DNA结合，并在特定的人类肿瘤中进行测试 系统，如乳腺癌和肺癌。 此外，我们正在设计 可能使这些药物在临床上 适用因 最后，我们正在扩大这些研究，包括其他 转录因子如CREB。

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.