Abstract
Expression and function of the oncogenic transcription factor activator protein (AP-1; mainly composed of Jun and Fos proteins) is required for neoplastic transformation of keratinocytes in vitro and tumor promotion as well as malignant progression in vivo. Here, we describe the identification of 372 differentially expressed genes comparing skin tumor samples of K5-SOS-F transgenic mice (Fos(f/f) SOS(+)) with samples derived from animals with a specific deletion of c-Fos in keratinocytes (Fos(Deltaep) SOS(+)). Fos-dependent transcription of selected genes was confirmed by quantitative real-time PCR analysis using tumor samples and mouse back skin treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). One of the most differentially expressed genes encodes the small mucin-like glycoprotein Podoplanin (Pdpn), whose expression correlates with malignant progression in mouse tumor model systems and human cancer. We found Pdpn and Fos expression in chemically induced mouse skin tumors, and detailed analysis of the Pdpn gene promoter revealed impaired activity in Fos-deficient mouse embryonic fibroblasts, which could be restored by ectopic Fos expression. Direct Fos protein binding to the Pdpn promoter was shown by chromatin immunoprecipitation and a TPA-induced complex at a TPA-responsive element-like motif in the proximal promoter was identified by electrophoretic mobility shift assays. In summary, we could define a Fos-dependent genetic program in a well-established model of skin tumors. Systematic analysis of these novel target genes will guide us in elucidating the molecular mechanisms of AP-1-regulated pathways that are critically implicated in neoplastic transformation and/or malignant progression.
Highlights
Cancer is a multistage disorder in which genetic and epigenetic changes result in characteristic alterations within the gene regulatory network and, thereby, influence the cellular decision of differentiation, proliferation, or survival [1]
Note: Supplementary data for this article are available at Cancer Research Online
We found several candidate genes with significantly higher transcript levels in the absence of Fos protein, and as an example, we analyzed Fos-dependent regulation of S100a3 transcription
Summary
Cancer is a multistage disorder in which genetic and epigenetic changes result in characteristic alterations within the gene regulatory network and, thereby, influence the cellular decision of differentiation, proliferation, or survival [1]. In the absence of Fos, tumor volume was significantly reduced, supporting the crucial role of Fos expression and activity for neoplastic transformation of epidermal keratinocytes.4 To identify tumor-associated genes whose expression critically depends on the presence of Fos function, we isolated total RNA from tumor samples of three independent Fos f/f SOS+ and FosDep SOS+ mice and performed global gene expression analysis.
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