ROLE OF AP-1 AND OTHER TRANSCRIPTION FACTORS IN CANCER CAUSE AND PREVENTION

本研究的总体目标是识别和表征基因 在肿瘤发生期间推动限速步骤的调节事件 促进和肿瘤进展。 AP-1转录因子是一种 Jun和Fos家族蛋白的异二聚体，其结合特异性的 某些基因转录启动子上的序列和驱动器 他们的转录。 我们1989年的观察（伯恩斯坦和科尔本， 科学，1989年），促进敏感（P+），但不是促进 抗性（P-）小鼠JB 6细胞通过以下方式对肿瘤促进剂作出应答： 激活AP-1依赖性转录，表明AP-1激活 可能需要从癌前病变进展为肿瘤 （肿瘤）表型。 对这一假设的初步检验表明， 药理学抑制剂、糖皮质激素和类维生素A， “基因治疗”抑制剂显性负性jun（TAM 67）阻断了这两种作用。 AP-1激活和转化反应。 这已经被延长了 表明转录因子特异性的类维生素A， AP-1活性无反式激活视黄酸反应元件 （RARE）依赖基因转录，也可预防肿瘤 转化（Li等人，Cancer Res，1996）。 所述显性负性 由角蛋白14（K14）启动子驱动的jun突变体（TAM 67）转基因， 当在小鼠角质形成细胞系308中表达时， 和NF κ B转录因子活性以及诱导的侵袭 到基质胶中（Dong等人，Molec.巨蟹座，在新闻界）建议 第二个转录因子NF κ B在这两个过程中可能的重要性 进展的原因和预防。 AP-1和NF κ B 活性和DNA结合显示在人类中逐渐升高， 角质形成细胞进展模型。 当转基因K14-TAM 67被 在更进展阶段的人类细胞系中表达， 肿瘤发生或锚定独立，肿瘤细胞表型是 抑制的（Li等人，正在筹备中）。 体内研究正在进行中。 TAM 67在小鼠JB 6 P+细胞中的表达产生表型逆转 当细胞在移植床上生长时， 例如，正在筹备中）。 表达K-14-TAM 67的转基因小鼠 已经产生了转基因。 两位创始人的后代将是 其特征在于可能保护皮肤免受刺激 致癌作用，即，预防癌前乳头状瘤形成。 因此，靶向转录因子AP-1和NF κ B似乎 有望用于癌症的预防和治疗。

The overall aim of this research is to identify and characterize gene regulation events that propel rate limiting steps during tumor promotion and tumor progression. The AP-1 transcription factor is a heterodimer of Jun and Fos family proteins that binds to a specific sequence on the transcriptional promoter of certain genes and drives their transcription. Our 1989 observation (Bernstein and Colburn, Science, 1989) that promotion sensitive (P+) but not promotion resistant (P-) mouse JB6 cells responded to tumor promoters by activating AP-1 dependent transcription, suggested that AP-1 activation might be required for progression from preneoplastic to neoplastic (tumor) phenotype. Initial testing of this hypothesis revealed that the pharmacologic inhibitors, glucocorticoids and retinoids and the "gene therapy" inhibitor dominant negative jun (TAM67) blocked both AP-1 activation and transformation response. This has been extended to show that transcription factor specific retinoids that transrepress AP-1 activity without transactivating retinoic acid response element (RARE) dependent gene transcription, also prevent neoplastic transformation (Li et al., Cancer Res, 1996). The dominant negative jun mutant (TAM67) transgene driven by a keratin 14 (K14) promoter, when expressed in a mouse keratinocyte line 308 suppressed both AP-1 and NFkapaB transcription factor activities as well as induced invasion into matrigel (Dong et al., Molec. Carcinog., in press) suggesting the possible importance of a second transcription factor NFkappaB in both the cause and prevention of progression. Both AP-1 and NFkappaB activities and DNA binding show progressive elevation in a human keratinocyte progression model. When the transgene K14-TAM67 is expressed in the more progressed stage human cell lines that are tumorigenic or anchorage independent, tumor cell phenotype is suppressed (Li et al., in preparation). In vivo studies are underway. Expression of TAM67 in mouse JB6 P+ cells produced phenotypic reversion to P- phenotype when cells were grown on a graft bed (Strickland et al., in preparation). Transgenic mice expressing the K-14-TAM67 transgene have been generated. Progeny of two founders will be characterized for possible protection against promotion of skin carcinogenesis, i.e., prevention of premalignant papilloma formation. Thus, targeting transcription factors AP-1 and NFkappaB appears promising for prevention and treatment of cancer.