The multistage mouse skin carcinogenesis model, although an artificial one, is an ideal system to study the timing of qualitative and quantitative alterations which take place during the different stages of chemical carcinogenesis, allowing analysis of the events that lead to the transition from the stage of initiation to the stage of promotion and finally to the progression of carcinogenesis. In this review we focus on the role of the H-ras gene and its target molecules during mouse skin carcinogenesis. Besides H-ras, which is a critical target of chemical carcinogens, we report alterations in oncosuppressor genes. Finally, we examine the potential suppression of metastatic dynamics of spindle cells after biological or chemical inhibition of the signalling cascades involved in mouse skin carcinogenesis.

Activating transcription factor (ATF)-2 is a member of the ATF/cyclic AMP-responsive element binding protein family of transcription factors. It has been shown, in vitro, to possess growth factor-independent proliferation and transformation capacity. The information concerning the involvement of ATF-2 in carcinogenesis is rather limited. In a previous report, we showed a progressive increase in the levels of various activator protein (AP)-1 components, including phosphorylated ATF-2, in a series of mouse skin cell lines that represented developmental stages of the mouse skin carcinogenesis system. In the present study, we examined in detail the role of ATF-2 in the development of mouse skin spindle cells A5 and CarB, which correspond to the late and most aggressive stage of the mouse skin carcinogenesis model. To address this issue, we overexpressed a dominant negative form of ATF-2 in the A5 and CarB cell lines and examined their behavior in vitro and in vivo at the molecular and cellular level. The stable transfectants expressed decreased levels of phosphorylated ATF-2 and c-Jun. Subsequently, we observed that dominant negative ATF-2 affected the composition and reduced the activity of AP-1. The above biochemical changes were followed, both in vitro and in vivo in BALB/c severe combined immunodeficient mice, by suppression of the aggressive characteristics of the A5 and CarB mouse skin spindle cells. We attributed this behavior to the significant down-regulation of cyclin D1, cyclin A, and ATF-3, known AP-1 targets implicated in cell cycle control and promotion. In conclusion, our findings underscore a key regulatory role of ATF-2 in tumor growth and progression of mouse skin tumors.

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