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).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010025-14
Application #
7965196
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2009
Total Cost
$651,408
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Perera, Thushanthi; Young, Matthew R; Zhang, Zhiying et al. (2015) Identification and monitoring of metabolite markers of dry bean consumption in parallel human and mouse studies. Mol Nutr Food Res 59:795-806
Saud, Shakir M; Li, Weidong; Morris, Nicole L et al. (2014) Resveratrol prevents tumorigenesis in mouse model of Kras activated sporadic colorectal cancer by suppressing oncogenic Kras expression. Carcinogenesis 35:2778-86
Narasimhan, Madhusudhanan; Rathinam, Marylatha; Riar, Amanjot et al. (2013) Programmed cell death 4 (PDCD4): a novel player in ethanol-mediated suppression of protein translation in primary cortical neurons and developing cerebral cortex. Alcohol Clin Exp Res 37:96-109
Wei, Qiou; Jiang, Hong; Baker, Alyson et al. (2013) Loss of sulfiredoxin renders mice resistant to azoxymethane/dextran sulfate sodium-induced colon carcinogenesis. Carcinogenesis 34:1403-10
Camalier, Corinne E; Yi, Ming; Yu, Li-Rong et al. (2013) An integrated understanding of the physiological response to elevated extracellular phosphate. J Cell Physiol 228:1536-50
Kang, Moon-Il; Baker, Alyson R; Dextras, Christopher R et al. (2012) Targeting of Noncanonical Wnt5a Signaling by AP-1 Blocker Dominant-Negative Jun When It Inhibits Skin Carcinogenesis. Genes Cancer 3:37-50
Mentor-Marcel, Roycelynn A; Bobe, Gerd; Sardo, Christine et al. (2012) Plasma cytokines as potential response indicators to dietary freeze-dried black raspberries in colorectal cancer patients. Nutr Cancer 64:820-5
Diyabalanage, Thushara; Ratnayake, Ranjala; Wilson, Jennifer A et al. (2011) Nothospondin, a new AP-1 inhibitory quassinoid from the Cameroonian plant Nothospondias staudtii. Bioorg Med Chem Lett 21:4397-9
Devkota, Krishna P; Ratnayake, Ranjala; Colburn, Nancy H et al. (2011) Inhibitors of the oncogenic transcription factor AP-1 from Podocarpus latifolius. J Nat Prod 74:374-7
Dong, Suwei; Cahill, Katharine J; Kang, Moon-Il et al. (2011) Microwave-based reaction screening: tandem retro-Diels-Alder/Diels-Alder cycloadditions of o-quinol dimers. J Org Chem 76:8944-54

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