SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IκB-α/NF-κB
Open Access
- 10 September 2007
- journal article
- Published by Rockefeller University Press in The Journal of cell biology
- Vol. 178 (6), 1009-1023
- https://doi.org/10.1083/jcb.200612067
Abstract
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.Keywords
This publication has 53 references indexed in Scilit:
- Oncogenic BRAF regulates β-Trcp expression and NF-κB activity in human melanoma cellsOncogene, 2006
- E3 Ubiquitin Ligases as Cancer Targets and BiomarkersNeoplasia, 2006
- Nuclear factor-κB in cancer development and progressionNature, 2006
- Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complexNature, 2002
- AP-1 in cell proliferation and survivalOncogene, 2001
- Elevated expression of SAG/ROC2/Rbx2/Hrt2 in human colon carcinomas: SAG does not induce neoplastic transformation, but antisense SAG transfection inhibits tumor cell growthMolecular Carcinogenesis, 2001
- The Hallmarks of CancerCell, 2000
- Mdm2 promotes the rapid degradation of p53Nature, 1997
- Keratins as biochemical markers of epithelial differentiationTrends in Genetics, 1988
- Comparison of the tumor-initiating activity of 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene in female SENCAR and CD-1 miceCarcinogenesis: Integrative Cancer Research, 1980