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SAG/ROC2/Rbx2 Is a Novel Activator Protein-1 Target that Promotes c-Jun Degradation and Inhibits 12-O-Tetradecanoylphorbol-13-Acetate–Induced Neoplastic Transformation

Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan

Requests for reprints: Yi Sun, Department of Radiation Oncology, University of Michigan, 4304 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0936. Phone: 734-615-1989; Fax: 734-647-9654; E-mail: sunyi{at}umich.edu.

SAG (sensitive to apoptosis gene) was first identified as a stress-responsive protein that, when overexpressed, inhibited apoptosis both in vitro and in vivo. SAG was later found to be the second family member of ROC1 or Rbx1, a RING component of SCF and DCX E3 ubiquitin ligases. We report here that SAG/ROC2/Rbx2 is a novel transcriptional target of activator protein-1 (AP-1). AP-1 bound both in vitro and in vivo to two consensus binding sites in a 1.3-kb region of the mouse SAG promoter. The SAG promoter activity, as measured by luciferase reporter assay, was dependent on these sites. Consistently, endogenous SAG is induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) with an induction time course following the c-Jun induction in both mouse epidermal JB6-Cl.41 and human 293 cells. TPA-mediated SAG induction was significantly reduced in JB6-Cl.41 cells overexpressing a dominant-negative c-Jun, indicating a requirement of c-Jun/AP-1. On the other hand, SAG seemed to modulate the c-Jun levels. When overexpressed, SAG remarkably reduced both basal and TPA-induced c-Jun levels, whereas SAG small interfering RNA (siRNA) silencing increased substantially the levels of both basal and TPA-induced c-Jun. Consistently, SAG siRNA silencing reduced c-Jun polyubiquitination and blocked c-Jun degradation induced by Fbw7, an F-box protein of SCF E3 ubiquitin ligase. Finally, SAG overexpression inhibited, whereas SAG siRNA silencing enhanced, respectively, the TPA-induced neoplastic transformation in JB6-Cl.41 preneoplastic model. Thus, AP-1/SAG establishes an autofeedback loop, in which on induction by AP-1, SAG promotes c-Jun ubiquitination and degradation, thus inhibiting tumor-promoting activity of AP-1. [Cancer Res 2007;67(8):3616–10]

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