SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IkappaB-alpha/NF-kappaB.
SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IkappaB-alpha/NF-kappaB.
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DOI：
10.1083/jcb.200612067
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发表时间：
2007-09-10
影响因子：
7.8
通讯作者：
Sun, Yi
中科院分区：
文献类型：
--
作者：
Gu, Qingyang;Bowden, G. Tim;Normolle, Daniel;Sun, Yi
细胞凋亡敏感基因（SAG）/cullins-2-Skp 1-cullin-F-box蛋白（SCF）调节因子E3泛素连接酶通过泛素化和蛋白底物的降解调节细胞功能。我们报告说，当在K14启动子驱动的小鼠表皮中表达时，SAG抑制TPA诱导的c-Jun水平和激活蛋白-1（AP-1）在体外原代培养物、体内转基因小鼠和AP-1荧光素酶报告小鼠模型中的活性。AP-1失活后，7，12-二甲基苯并（a）-蒽/12-O-十四酰佛波醇-13-乙酸酯在癌变早期诱导的表皮增殖基本上受到抑制。晚期肿瘤形成也受到显著抑制，潜伏期延长，肿瘤形成频率降低。有趣的是，SAG表达增加了肿瘤大小，不是因为加速增殖，而是由减少的细胞凋亡引起的，至少部分是由核因子κB（NF-κB）激活引起的。因此，SAG以依赖于F-box蛋白的可用性的方式，通过促进c-Jun降解从而抑制AP-1而表现出对肿瘤形成的早期抑制，并且通过促进κBα抑制剂降解以激活NF-κB并抑制细胞凋亡而表现出对肿瘤生长的后期增强。
Sensitive to apoptosis gene (SAG)/regulator of cullins-2–Skp1-cullin–F-box protein (SCF) E3 ubiquitin ligase regulates cellular functions through ubiquitination and degradation of protein substrates. We report that, when expressed in mouse epidermis driven by the K14 promoter, SAG inhibited TPA-induced c-Jun levels and activator protein-1 (AP-1) activity in both in vitro primary culture, in vivo transgenic mice, and an AP-1– luciferase reporter mouse model. After AP-1 inactivation, epidermal proliferation induced by 7,12-dimethylbenz(a)-anthracene/12-O-tetradecanoylphorbol-13-acetate at the early stage of carcinogenesis was substantially inhibited. Later stage tumor formation was also substantially inhibited with prolonged latency and reduced frequency of tumor formation. Interestingly, SAG expression increased tumor size, not because of accelerated proliferation, but caused by reduced apoptosis resulting, at least in part, from nuclear factor κB (NF-κB) activation. Thus, SAG, in a manner depending on the availability of F-box proteins, demonstrated early-stage suppression of tumor formation by promoting c-Jun degradation, thereby inhibiting AP-1, and later-stage enhancement of tumor growth, by promoting inhibitor of κBα degradation to activate NF-κB and inhibit apoptosis.
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影响因子：
56.9
作者：
Nateri, AS;Riera-Sans, L;Behrens, A
通讯作者：
Behrens, A
DOI：
10.1073/pnas.91.2.609
发表时间：
1994-01-18
影响因子：
11.1
作者：
DONG, ZG;BIRRER, MJ;COLBURN, NH
通讯作者：
COLBURN, NH
影响因子：
4.7
作者：
HENNINGS, H;GLICK, AB;YUSPA, SH
通讯作者：
YUSPA, SH
DOI：
10.1073/pnas.0510422103
发表时间：
2006-02-14
影响因子：
11.1
作者：
Kobielak, A;Fuchs, E
通讯作者：
Fuchs, E
影响因子：
8
作者：
Liu, J.;Kumar, K. G. Suresh;Fuchs, S. Y.
通讯作者：
Fuchs, S. Y.