Carcinogenesis Advance Access originally published online on February 6, 2008
Carcinogenesis 2008 29(4):858-865; 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
* To whom correspondence should be addressed. Tel: +1 734 615 1989; Fax: +1 734 647 9654; Email: sunyi{at}umich.edu
Sensitive to apoptosis gene (SAG)/regulator of cullins-2/RING box protein 2 is a stress-responsive RING component of Skp-1/Cullins/F-box protein E3 ubiquitin ligase. When overexpressed, SAG inhibits apoptosis induced by reactive oxygen species or hypoxia. Here, we report that SAG overexpression inhibits ultraviolet (UV) B-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 (antiproliferation) increased skin hyperplasia, with no apparent effect on apoptosis, as evidenced by increased skin thickness, and 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.
Abbreviations: BrdU, 5-bromo-2'-deoxy-uridine; PFA, paraformaldehyde; ROC/RBX, Regulator of Cullins/RING box protein; SAG, sensitive to apoptosis gene; SCF, Skp1-Cullins-F-box protein; SiRNA, small interfering RNA; TUNEL, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling; UV, ultraviolet
These authors contributed equally to this work. Received October 7, 2007; revised December 20, 2007; accepted January 12, 2008.