The Role of AP-1 and Other Transcription Factors in Cancer Cause and Prevention

AP-1转录因子是Jun和Fos家族蛋白的异源二聚体， 与某些基因的转录启动子上的特定序列结合，并驱动它们的 转录。AP-1活性在几种人类癌症的肿瘤进展期间升高 网站.显性负性Jun基因在转基因小鼠角质形成细胞中的特异性表达 诱导AP-1和肿瘤发生，而不抑制细胞增殖或细胞存活。 与人类致癌作用相关的多种小鼠模型（Young等，PNAS，1999）。其中 是皮肤肿瘤促进反应因人乳头状瘤表达而升高的小鼠。 病毒E7（Young等Molec Carc 2002）和通过以下方法诱导形成鳞状细胞癌的小鼠 重复暴露于UVB（库珀等人Molec癌症研究，2003）。四环素管制 TAM 67的表达最近在实验室中被定向到乳腺上皮细胞， 合作者Powel Brown（Shen et al Dev Biol 2006），并正在测试其在 预防HER 2/Neu诱导的乳腺癌发生。转录因子NF κ B是 与AP-1协调调节，表明这两种因子在 转化（Li et，Cancer Res 1997）。最近的观察发现NFkB 非响应性作为JB 6模型中转换非响应性的解释 (Hsu等人，Cancer Res 2001，Hu等人Carcinogenesis 2004）。转化抗性细胞 它们对不能激活NF κ B B p65蛋白的无反应性。p65磷酸化 在S536处对于DNA结合以及抑制剂的泛素化和降解是重要的 IkappaB α（Hu et al Molec Carcinog 2005）。针对AP-1和NFkB的观察 升高阻止肿瘤促进和进展已经从小鼠JB 6模型扩展 涉及小鼠和人角质形成细胞进展模型以及转基因小鼠模型。转基因 表达AP-1/ NFkB抑制剂TAM 67的小鼠提供了鉴定AP-1或 NFkB靶基因，其表达对肿瘤转化至关重要。表达 微阵列分析揭示了TAM 67靶基因，这些基因正在被查询功能， 在致癌作用中的重要性。这些靶基因可能是有前途的新分子生物学靶点。 用于癌症预防的靶点（Young等Trends in Molec Medicine 2003）。最近的研究 确立了染色质结构蛋白HMGA 1的重要性（达尔等人，Oncogene 2004）、考克斯-2和骨桥蛋白（马修斯等Cancer Res 2007）作为功能显著的 TAM 67目标。与分子靶点合作的一个有前途的药物发现项目 开发计划旨在鉴定模拟TAM 67特异性的化合物，即 防止肿瘤发生而不抑制细胞增殖或细胞存活。小学高 300，000合成和天然产物的通量筛选与细胞增殖偶联 (XTT)测定产生一小组命中（Ruocco等J Biomolec Screening 2007）。第二试验评估NFkB的抑制。新的干预研究 在遗传肥胖小鼠中，采用基于豆类的饮食进行结肠衰减测试， 氧化偶氮甲烷致癌作用。以豆类为基础的饮食被选择来模仿 在最近完成的息肉预防试验中， 最高四分位数的豆类（海军蓝，利马，肾脏，黑色等）显示出3倍的减少， 晚期腺瘤（E.兰扎和同事）。整个豆子和两个豆子部分 显示出减弱肿瘤多样性的功效（Bobe等人，提交）。目前的研究是 目的是确定功能上重要的分子目标的豆类饮食下， 疗效状况以及预测性生物标志物。

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. AP-1 activity is elevated during tumor progression in several human cancer sites. Keratinocyte-specific expression of Dominant Negative Jun in transgenic mice inhibits induced AP-1 and tumorigenesis without inhibiting cell proliferation or cell survival in multiple mouse models relevant to human carcinogenesis (Young et al., PNAS, 1999). Among these are mice whose skin tumor promotion response is elevated by expression of Human Papilloma Virus E7 (Young et al Molec Carc 2002) and mice induced to form squamous carcinomas by repeated exposure to UVB (Cooper et al Molec Cancer Res 2003). Tetracycline regulated expression of TAM 67 has recently been directed to mammary epithelia in the laboratory of collaborator Powel Brown (Shen et al Dev Biol 2006) and is being tested for efficacy in preventing HER2/Neu induced mammary carcinogenesis. The transcription factor NFkappa B is coordinately regulated with AP-1, suggesting the possible importance of both factors in transformation (Li et, Cancer Res 1997). Recent observations have identified NFkB non-responsiveness as an explanation for transformation non-responsiveness in the JB6 model (Hsu et al, Cancer Res 2001, Hu et al Carcinogenesis 2004). Transformation resistant cells owe their nonresponsiveness to an inability to activate NFkappa B p65 protein. p65 phosphorylation at S536 is important for DNA binding and for ubiquitination and degradation of inhibitor IkappaB alpha (Hu et al Molec Carcinog 2005). The observation that targeting AP-1 and NFkB elevation prevents tumor promotion and progression has been extended from the mouse JB6 model to mouse and human keratinocyte progression models, and to transgenic mouse models. Transgenic mice expressing AP-1/ NFkB inhibitor TAM 67 present a valuable opportunity to identify AP-1 or NFkB target genes whose expression is critical to neoplastic transformation. Expression microarray analysis has revealed TAM67 target genes that are being queried for functional significance in driving carcinogenesis. Such target genes may be promising new molecular targets for cancer prevention (Young et al Trends in Molec Medicine 2003). Recent studies have established the importance of chromatin architectural protein HMGA1 (Dhar et al Oncogene 2004), COX-2, and osteopontin (Matthews et al Cancer Res 2007) as functionally significant TAM67 targets. A promising drug discovery project in collaboration with the Molecular Targets Development Program aims to identify compounds that mimic the specificity of TAM67, i.e. that prevent tumorigenesis without inhibiting cell proliferation or cell survival. The primary high throughput screen of 300,000 synthetic and natural products coupled to a cell proliferation (XTT) assay yielded a small set of hits (Ruocco et al J Biomolec Screening 2007). The secondary assay is assessing inhibition of NFkB. New intervention studies in genetically obese mice employ a bean-based diet being tested for attenuation of colon carcinogenesis following exposure to azoxymethane. The bean-based diet was chosen to mimic conditions in the recently completed polyp prevention trial in which human subjects consuming the highest quartile of beans (navy, lima, kidney, black etc) showed a 3-fold reduction in ocurrence of advanced adenoma (E. Lanza and coworkers). The whole beans and two bean fractions showed efficacy in attenuating tumor multiplicity (Bobe et al, submitted). Current studies are aimed at identifying funtionally significant molecular targets of the bean diets under conditions of efficacy as well as predictive biomarkers.