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

点击翻译按钮获取中文摘要

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.