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PMID:15047715

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Citation

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

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.

Links

PubMed Online version:10.1074/jbc.M400516200

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:WWP2

located_in

GO:0005737: cytoplasm

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9DBH0

C

Seeded From UniProt

complete

MOUSE:PO5F1

involved_in

GO:0006357: regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WWP2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:WWP2

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:WWP2

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P20263)

Seeded From UniProt

complete

HUMAN:WWP2

part_of

GO:0005737: cytoplasm

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9DBH0

C

Seeded From UniProt

complete

HUMAN:WWP2

enables

GO:0001085: RNA polymerase II transcription factor binding

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9DBH0

F

Seeded From UniProt

complete

HUMAN:WWP2

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9DBH0

P

Seeded From UniProt

complete

HUMAN:WWP2

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9DBH0

P

Seeded From UniProt

complete

HUMAN:WWP2

involved_in

GO:0043433: negative regulation of DNA-binding transcription factor activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9DBH0

P

Seeded From UniProt

complete

MOUSE:WWP2

GO:0001085: RNA polymerase II transcription factor binding

ECO:0000021:

UniProtKB:P20263


F

fig 3a

complete

MOUSE:WWP2

GO:0004842: ubiquitin-protein ligase activity

ECO:0000021:

UniProtKB:P20263


F

Fig 5a 5b Wwp2 promotes ubiquitination of Oct-4.

complete

MOUSE:WWP2

GO:0005634: nucleus

ECO:0000314:

C

fig 2b. Es cells were stained with propidium iodide to highlight nucleus

complete

MOUSE:WWP2

GO:0005737: cytoplasm

ECO:0000314:

C

fig 2b

complete

MOUSE:WWP2

GO:0016481: negative regulation of transcription

ECO:0000314:

P

fig 7. Wwp2 inhibits transcriptional activity of Oct-4.

complete

MOUSE:WWP2

enables

GO:0001085: RNA polymerase II transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P20263

F

Seeded From UniProt

complete

MOUSE:WWP2

involved_in

GO:0016567: protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WWP2

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WWP2

involved_in

GO:0043433: negative regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WWP2

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:WWP2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:WWP2

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

has_direct_input:(UniProtKB:P20263)

Seeded From UniProt

complete

MOUSE:WWP2

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PO5F1

GO:0031625: ubiquitin protein ligase binding

ECO:0000021:

UniProtKB:Q9DBH0


F

Fig 3. Wwp2 binds oct4 both in vitro and in vivo

complete

MOUSE:PO5F1

GO:0005634: nucleus

ECO:0000314:

C

fig 2b

complete

MOUSE:PO5F1

GO:0045941: positive regulation of transcription

ECO:0000269:

P

fig 6

complete

MOUSE:PO5F1

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PO5F1

involved_in

GO:0042789: mRNA transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PO5F1

enables

GO:0031625: ubiquitin protein ligase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9DBH0

F

Seeded From UniProt

complete

MOUSE:PO5F1

involved_in

GO:0006366: transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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