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Xu, HM, Liao, B, Zhang, QJ, Wang, BB, Li, H, Zhong, XM, Sheng, HZ, Zhao, YX, Zhao, YM and Jin, Y (2004) Wwp2, an E3 ubiquitin ligase that targets transcription factor Oct-4 for ubiquitination. J. Biol. Chem. 279:23495-503
The POU transcription factor Oct-4 is a master regulator affecting the fate of pluripotent embryonic stem cells. However, the precise mechanisms by which the activation and expression of Oct-4 are regulated still remain to be elucidated. We describe here a novel murine ubiquitin ligase, Wwp2, that specifically interacts with Oct-4 and promotes its ubiquitination both in vivo and in vitro. Remarkably, the expression of a catalytically inactive point mutant of Wwp2 abolishes Oct-4 ubiquitination. Moreover, Wwp2 promotes Oct-4 degradation in the presence of overexpressed ubiquitin. The degradation is blocked by treatment with proteasome inhibitor. Fusion of a single ubiquitin to Oct-4 inactivates its transcriptional activity in a heterologous Oct-4-driven reporter system. Furthermore, overexpression of Wwp2 in embryonic stem cells significantly reduces the Oct-4-transcriptional activities. Collectively, we demonstrate for the first time that Oct-4 can be post-translationally modified by ubiquitination and that this modification dramatically suppresses its transcriptional activity. These results reveal that the functional status of Oct-4, in addition to its expression level, dictates its transcriptional activity, and the results open up a new avenue to understand how Oct-4 defines the fate of embryonic stem cells.
Animals; Cell Differentiation; DNA-Binding Proteins/metabolism; Mice; Octamer Transcription Factor-3; Protein Binding; Signal Transduction; Stem Cells/metabolism; Transcription Factors/metabolism; Ubiquitin-Protein Ligases/metabolism; Ubiquitins/metabolism