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 与PowelBrown合作，TAM 67的表达已被导向乳腺上皮 (Shen等人Dev Biol 2006），并且最近已经测试了在预防HER 2/Neu 诱发乳腺癌。结果显示AP-1阻断剂对 癌前以及早期和晚期肿瘤发展（Shen等Ca Prev Res 2008年）。重要的是，TAM 67表达在发生的乳腺肿瘤中沉默。的 转录因子NF κ B B与AP-1协同调节，提示可能的 这两个因素在转化中的重要性（Li et，Cancer Res 1997）。最近的观察 已经将NFkB无反应性确定为转化的解释 JB 6模型中的无反应性（Hsu等，Cancer Res 2001，Hu等Carcinogenesis 2004年）。转化抗性细胞的无反应性归因于不能激活 NF κ B B p65蛋白。p65在S536处的磷酸化对于DNA结合和 抑制剂IkappaB α的泛素化和降解（Hu et al Molec Carcinog 2005）。的 观察到靶向AP-1和NFkB升高可预防肿瘤促进和进展 已经从小鼠JB 6模型扩展到小鼠和人角质形成细胞进展模型， 以及转基因小鼠模型。存在表达AP-1/ NFkB抑制剂TAM 67的转基因小鼠 一个宝贵的机会，以确定AP-1或NF κ B的目标基因的表达是至关重要的， 肿瘤性转化表达微阵列分析揭示了TAM 67靶基因， 在致癌过程中的功能意义受到质疑。这些靶基因可以 是预防癌症的有希望的新分子靶点（Young等人Trends in Molec Medicine 2003年）。最近的研究已经确定了染色质结构蛋白HMGA 1的重要性 (Dhar等Oncogene 2004）、考克斯-2、骨桥蛋白、尿激酶纤溶酶原激活剂、Cxcl 1和 MMP-10（马修斯等Cancer Res 2007）作为功能上重要的TAM 67靶标。最 最近发现的TAM 67/AP-1靶基因是sulfiredoxin，一种氧化还原酶， 在肿瘤促进和侵袭中具有功能意义， 癌症（Wei Q等人，PNAS 2008）。与分子生物学合作的药物发现项目 目标开发计划已经鉴定了模拟TAM 67特异性的化合物，即 其抑制AP-1和/或NFkB并防止癌发生而不抑制细胞增殖 或细胞存活。初级AP-1高通量筛选30万合成和天然 与细胞增殖（XTT）测定偶联的产物产生了一小组 命中（Ruocco等人J Biomolec Screening 2007年）。二次试验评估了NFkB的抑制作用，并鉴定了AP-1抑制剂 其对NF κ B甚至更有活性（Kang等人，Mol Ca Ther，2009）。

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 been directed to mammary epithelia in collaboration with Powel Brown (Shen et al Dev Biol 2006) and has recently been tested for efficacy in preventing HER2/Neu induced mammary carcinogenesis. The results show substantial inhibition by the AP-1 blocker of preneoplastic as well as early and later stage tumor development (Shen et al Ca Prev Res 2008). Importantly, TAM67 expression was silenced in mammary tumors that developed. 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, osteopontin, urokinase plasminogen activator, Cxcl1 and MMP-10 (Matthews et al Cancer Res 2007) as functionally significant TAM67 targets. The most recently discovered TAM67/AP-1 target gene is sulfiredoxin, a redox enzyme that is functionally significant both in tumor promotion and invasion as well as elevated in human cancer (Wei Q, et al, PNAS 2008). A drug discovery project in collaboration with the Molecular Targets Development Program has identified compounds that mimic the specificity of TAM67, i.e. that inhibit AP-1 and/or NFkB and prevent carcinogenesis without inhibiting cell proliferation or cell survival. The primary AP-1 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 has assessed inhibition of NFkB and identified an AP-1 inhibitor that is even more active against NFkappa B (Kang et al Mol Ca Ther, 2009).