The Role of AP-1 and Other Transcription Factors in Canc

AP-1转录因子是Jun和Fos家族蛋白的异源二聚体，其与某些基因的转录启动子上的特定序列结合并驱动其转录。转基因小鼠中显性阴性Jun的角质细胞特异性表达抑制诱导的AP-1和肿瘤发生，而不抑制与人类致癌相关的多种小鼠模型中的细胞增殖或细胞存活（Young等人，PNAS，1999）。其中包括皮肤肿瘤促进反应因人乳头瘤病毒E7的表达而升高的小鼠（Young等Molec Carc 2002）和通过反复暴露于UVB而诱导形成鳞状细胞癌的小鼠（库珀等Molec Cancer Res 2003）。最近，在合作者Powel Brown的实验室中，四环素调节的TAM 67表达已被导向乳腺上皮细胞（Shen et al Dev Biol 2006），并正在测试其预防HER 2/Neu诱导的乳腺癌发生的功效。转录因子NF κ B与AP-1协同调节，表明两种因子在转化中的可能重要性（Li et，Cancer Res 1997）。最近的观察已经将NFkB无应答性鉴定为JB 6模型中转化无应答性的解释（Hsu等，Cancer Res 2001，Hu等Carcinogenesis 2004）。转化抗性细胞的无应答性归因于不能激活NF κ B p65蛋白。在S536处的p65磷酸化对于DNA结合和抑制剂IkappaB α的泛素化和降解都是重要的（Hu et al Molec Carcinog 2005）。靶向AP-1和NFkB升高阻止肿瘤促进和进展的观察结果已从小鼠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。表达AP-1/ NFkB抑制剂TAM 67的转基因小鼠提供了鉴定AP-1或NFkB靶基因的宝贵机会，所述靶基因的表达对于肿瘤转化是关键的。表达微阵列分析揭示了TAM 67靶基因，这些靶基因正在被质疑在驱动癌发生中的功能意义。这样的靶基因可能是用于癌症预防的有希望的新分子靶标（Young等Trends in Molec Medicine 2003）。最近的研究已经确定了染色质结构蛋白HMGA 1（达尔等人Oncogene 2004）、考克斯-2和骨桥蛋白（马修斯等人提交）作为功能上重要的TAM 67靶标的重要性。与分子靶标开发计划合作的一个有前途的药物发现项目旨在鉴定模拟TAM 67特异性的化合物，即在不抑制细胞增殖或细胞存活的情况下预防肿瘤发生。对300，000种合成和天然产物的初级高通量筛选与细胞增殖（XTT）测定偶联，产生了一小组“命中”（Ruocco等人，出版中）。第二次试验将评估NFkB的抑制。

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. 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 both 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 submitted) 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 has yielded a small set of "hits" (Ruocco et al in press). The secondary assay will assess inhibition of NFkB.