Carcinogenesis Advance Access published online on February 6, 2008
Carcinogenesis, doi:10.1093/carcin/bgn021
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SAG/ROC2/RBX2 E3 ligase promotes UVB-induced skin hyperplasia, but not skin tumors, by simultaneously targeting c-Jun/AP-1 and p27
Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor MI 48109, USA
# Corresponding author: Yi Sun, Tel. 734-615-1989; Fax 734-647-9654; Email: sunyi{at}umich.edu
SAG (Sensitive to Apoptosis Gene)/ROC2 (Regulator of Cullins-2)/Rbx2 (RING box protein-2) is a stress-responsive RING component of SCF (Skp-1/Cullins/F box proteins) E3 ubiquitin ligase. When over-expressed, SAG inhibits apoptosis induced by ROS (Reactive oxygen species) or hypoxia. Here we report that SAG over-expression inhibits UVB-induced apoptosis in mouse JB6 epidermal cells. Using a transgenic mouse model, in which SAG expression was targeted primarily to epidermis by a K14 promoter, we showed that, at the early stage of UVB skin carcinogenesis (10 weeks post UVB exposure), c-Jun, p27, p53, c-fos and cyclin D1 were strongly induced. While having no effect on UVB-induced p53, c-fos and cyclin D1, SAG transgenic expression reduced the levels of c-Jun and p27 and inhibited AP-1 activity. The net outcome of SAG-mediated inhibition of c-Jun/AP-1 (pro-tumor promotion) and of p27 (anti-proliferation) was increased skin hyperplasia, with no apparent effect on apoptosis, as evidenced by increased skin thickness, increased rate of DNA synthesis, but hardly any apoptosis. Although skin hyperplasia was promoted, SAG transgenic expression had no significant effect on tumor formation in the later stage of UVB carcinogenesis. Thus, by simultaneously targeting c-Jun and p27, SAG accelerates UVB-induced skin hyperplasia, but not carcinogenesis.
Key Words: c-Jun/AP-1 • p27 • SAG-SCF E3 ligase • UVB skin hyperplasia and carcinogenesis
* These authors contributed equally to this work
Received October 7, 2007; revised December 20, 2007; accepted January 12, 2008.