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 observations with mouse JB6 cells and with an engineered mouse model (Bernstein and Colburn, Science, 1989, Dong et al PNAS, 1994, Young et al., PNAS, 1999) established that AP-1 activation is required for skin tumorigenesis and tumor progression. Keratinocyte-specific expression of Dominant Negative Jun in transgenic mice inhibits induced AP-1 and tumorigenesis without inhibiting growth, differentiation or hyperplasia in multiple mouse models relevant to human carcinogenesis. 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). For further studies, tetracycline regulated expression of TAM 67 is being directed to mammary and lung epithelia in the laboratories of collaborators Powel Brown and Jay Tischlaar. When the transgene K14-TAM67 or a tetracycline regulated TAM67 construct was expressed in the more progressed human cell lines that are tumorigenic or anchorage independent and show elevated AP-1 and NFkB activities, tumor cell phenotype was suppressed (Li et al., Oncogene, 1998 and Li et al., Molec Carcinog 2000). 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 transformation 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). Thus 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. New understanding of critical molecular interactions is emerging. 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 potential TAM67 target genes that are subjects of current research. Such target genes may be promising new molecular targets for cancer prevention (Young et al Trends in Molec Medicine 2003). Recent studies have excluded iNOS (Dhar et al Mol Cancer Ther 2003)and other studies have established the importance of chromatin architectural protein HMGA1(Dhar et al Oncogene 2004) as a functionally significant TAM67 target. Research directed to identifying MAP kinase ERK dependent molecular events required for activating AP-1 has identified the activation of Fos family protein Fra-1 as a pivotal event (Young et al, Molec Cell Biol 2002). JB6 variants deficient in either Erk or Fra-1 proteins are AP-1 and transformation nonresponsive. Responsiveness is restored by expression of Erk or Fra-1 respectively. A subset of AP-1 dependent gene promoters is expected to require Fra-1 for transcriptional activation and these may serve as particularly effective targets for cancer prevention.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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Bobe, Gerd; Barrett, Kathleen G; Mentor-Marcel, Roycelynn A et al. (2008) Dietary cooked navy beans and their fractions attenuate colon carcinogenesis in azoxymethane-induced ob/ob mice. Nutr Cancer 60:373-81
Bobe, Gerd; Sansbury, Leah B; Albert, Paul S et al. (2008) Dietary flavonoids and colorectal adenoma recurrence in the Polyp Prevention Trial. Cancer Epidemiol Biomarkers Prev 17:1344-53
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