PMID:19274063

Citation	Xu, H, Wang, W, Li, C, Yu, H, Yang, A, Wang, B and Jin, Y (2009) WWP2 promotes degradation of transcription factor OCT4 in human embryonic stem cells. Cell Res. 19:561-73
Abstract	POU transcription factor OCT4 not only plays an essential role in maintaining the pluripotent and self-renewing state of embryonic stem (ES) cells but also acts as a cell fate determinant through a gene dosage effect. However, the molecular mechanisms that control the intracellular OCT4 protein level remain elusive. Here, we report that human WWP2, an E3 ubiquitin (Ub)-protein ligase, interacts with OCT4 specifically through its WW domain and enhances Ub modification of OCT4 both in vitro and in vivo. We first demonstrated that endogenous OCT4 in human ES cells can be post-translationally modified by Ub. Furthermore, we found that WWP2 promoted degradation of OCT4 through the 26S proteasome in a dosage-dependent manner, and the active site cysteine residue of WWP2 was required for both its enzymatic activity and proteolytic effect on OCT4. Remarkably, our data show that the endogenous OCT4 protein level was significantly elevated when WWP2 expression was downregulated by specific RNA interference (RNAi), suggesting that WWP2 is an important regulator for maintaining a proper OCT4 protein level in human ES cells. Moreover, northern blot analysis showed that the WWP2 transcript was widely present in diverse human tissues/organs and highly expressed in undifferentiated human ES cells. However, its expression level was quickly decreased after human ES cells differentiated, indicating that WWP2 expression might be developmentally regulated. Our findings demonstrate that WWP2 is an important regulator of the OCT4 protein level in human ES cells.
Links	PubMed Online version:10.1038/cr.2009.31
Keywords	Cell Differentiation; Down-Regulation; Embryonic Stem Cells/enzymology; Humans; Octamer Transcription Factor-3/metabolism; Proteasome Endopeptidase Complex/metabolism; RNA Interference; Ubiquitin-Protein Ligases/metabolism; Ubiquitination
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:WWP2	located_in	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:WWP2	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q01860	F	occurs_in:(GO:0005634)	Seeded From UniProt	complete
HUMAN:PO5F1	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O00308	F	occurs_in:(GO:0005634)	Seeded From UniProt	complete
HUMAN:PO5F1	located_in	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:WWP2	enables	GO:0001085: RNA polymerase II transcription factor binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q01860	F		Seeded From UniProt	complete
HUMAN:WWP2	involved_in	GO:0000122: negative regulation of transcription by RNA polymerase II	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:WWP2	involved_in	GO:0043161: proteasome-mediated ubiquitin-dependent protein catabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:WWP2	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:WWP2	enables	GO:0004842: ubiquitin-protein transferase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:PO5F1	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:PO5F1	enables	GO:0031625: ubiquitin protein ligase binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O00308	F		Seeded From UniProt	complete

References

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