title: Wwp2, an E3 ubiquitin ligase that targets transcription factor Oct-4 for ubiquitination.
abstract: 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.
authors.affiliation: Developmental Biology Department, Health Science Center, Shanghai Second Medical University and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 411 He Fei Road, Shanghai 200025, China.
authors.forename: Hui Ming
authors.initials: HM
authors.lastname: Xu
authors.forename: Bing
authors.initials: B
authors.lastname: Liao
authors.forename: Qian Jun
authors.initials: QJ
authors.lastname: Zhang
authors.forename: Bei Bei
authors.initials: BB
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Xiao Min
authors.initials: XM
authors.lastname: Zhong
authors.forename: Hui Zhen
authors.initials: HZ
authors.lastname: Sheng
authors.forename: Ying Xin
authors.initials: YX
authors.lastname: Zhao
authors.forename: Ying Ming
authors.initials: YM
authors.lastname: Zhao
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051379:Mice; D050814:Octamer Transcription Factor-3; D011485:Protein Binding; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D014157:Transcription Factors; D014452:Ubiquitins; C487995:Wwp2 protein, mouse; D044767:Ubiquitin-Protein Ligases