Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are ubiquitous complete carcinogens that are present in tobacco smoke. The majority of work in previous studies has focused on the mutations that are associated with the tumor initiation effect of these compounds. However, the tumor promotion effect of PAHs, which is thought to be mediated through regulation of signal transduction pathways leading to activation of transcription factors, remains unclear. Our preliminary studies suggest that benzo[a]pyrene diol-epoxide (B[a]PDE), an ultimate carcinogenic metabolite of benzo[a]pyrene (B[a]P), is a major compound responsible for activation of the transcription factor activator protein-1 (AP-1) in non-cytotoxic concentrations. Since growing evidence has shown that activation of AP-1 by carcinogens is required for tumor promotion in both cell culture models and animal experiments, the main hypothesis of this proposal is that signal transduction pathways leading to activation of AP-1 play a critical role in the tumor promotion effect induced by B[a]PDE. The overall aim of this proposal is to elucidate the molecular mechanisms by which PAHs induce tumor promotion. Especially, we will establish the signal transduction pathways leading to AP-1 activation by B[a]PDE in a well-characterized tumor promotion cell culture model, mouse epidermal C141 cells. We will then investigate whether the same pathway occurs in an in vivo model using an AP-1-luciferase reporter transgenic mouse model. Furthermore, we will determine the role of AP-1 activation in B[a]PDE-induced tumor promotion in a two-stage carcinogenesis mouse skin model using dominant negative mutant c-jun (TAM67) transgenic mice. We will investigate these issues in accordance with the following testable hypotheses and specific aims: 1) To elucidate early events involved in initiating the signaling pathways leading to AP-1 activation by B[a]PDE in mouse epidermal C141 cells; 2) To test the hypothesis that the PI-3K/Akt/p7086k pathway is required for B[a]PDE-induced AP-1 activation in mouse epidermal C141 cells; 3) To determine whether B[a]PDE is able to induce AP-1 activation in vivo by using AP-1-luciferase reporter transgenic mice and whether this activation is through the same signal transduction pathways as in vitro; 4) To test the hypothesis that AP-1 activation is essential in the tumor promotion effect of B[a]PDE in a two-stage carcinogenesis mouse model. The significance of the research proposed in this application is that the results derived from the proposed studies will greatly facilitate the understanding of the molecular mechanism of cancer development caused by B[a]P and B[a]PDE. A better understanding of signal transduction pathways leading to AP-1 induction may provide valuable information needed for designing more effective agents for prevention and therapy of cancers caused by cigarette smoke. Such agents could interfere with the signaling pathways leading to AP-1 activation.
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