SAG/ROC2/RBX2 E3 ligase promotes UVB-induced skin hyperplasia, but not skin tumors, by simultaneously targeting c-Jun/AP-1 and p27.
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.
He
Hongbin
H
Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
Gu
Qingyang
Q
Zheng
Min
M
Normolle
Daniel
D
Sun
Yi
Y
D000818:Animals; D002460:Cell Line; D004817:Epidermis / Q000502:physiology; D006801:Humans; D006965:Hyperplasia; D020287:In Situ Nick-End Labeling; D007633:Keratins / Q000235:genetics; D008168:Lung; D051379:Mice; D008822:Mice, Transgenic; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011877:Radionuclide Imaging; D012867:Skin / Q000166:cytology / Q000473:pathology* / Q000528:radiation effects; D012878:Skin Neoplasms / Q000000981:diagnostic imaging; D018808:Transcription Factor AP-1 / Q000378:metabolism* / Q000528:radiation effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D014466:Ultraviolet Rays
D018809:Proliferating Cell Nuclear Antigen; D018808:Transcription Factor AP-1; C413374:p27 antigen; D007633:Keratins; C118307:RNF7 protein, human; D044767:Ubiquitin-Protein Ligases