ARF-BP1/mule is a critical mediator of the ARF tumor suppressor

作者：Chen DL; Kon N; Li MY; Zhang WZ; Qin J; Gu W^*

来源：Cell, 2005, 121(7): 1071-1083.

DOI：10.1016/j.cell.2005.03.037

Although the importance of the ARF tumor suppressor in p53 regulation is well established, numerous studies indicate that ARF also suppresses cell growth in a p53/Mdm2-independent manner. To understand the mechanism of ARF-mediated tumor suppression we identified a ubiquitin ligase, ARF-BP1, as a key factor associated with ARF in vivo. ARF-BP1 harbors a signature HECT motif, and its ubiquitin ligase activity is inhibited by ARK Notably, inactivation of ARFBP1, but not Mdm2, suppresses the growth of p53 null cells in a manner reminiscent of ARF induction. Surprisingly, in p53 wild-type cells, ARF-BP1 directly binds and ubiquitinates p53, and inactivation of endogenous ARF-BP1 is crucial for ARF-mediated p53 stabilization. Thus, our study modifies the current view of ARF-mediated p53 activation and reveals that ARF-BP1 is a critical mediator of both the p53-independent and p53-dependent tumor suppressor functions of ARE As such, ARF-BP1 may serve as a potential target for therapeutic intervention in tumors regardless of p53 status.

• 出版日期2005-7-1