An oncogenic mutation uncouples the v-Jun oncoprotein from positive regulation by the SAPK/JNK pathway in vivo.
Curr Biol
; 8(2): 117-20, 1998 Jan 15.
Article
in En
| MEDLINE
| ID: mdl-9427647
ABSTRACT
Stimulation of c-Jun transcriptional activity via phosphorylation mediated by the stress-activated or c-Jun amino-terminal (SAPK/JNK) subgroup of mitogen-activated protein kinases (MAP kinases) is thought to depend on a kinase-docking site (the delta region) within the amino-terminal activation domain, which is deleted from the oncogenic derivative, v-Jun [1] [2] [3]. This mutation markedly enhances v-Jun oncogenicity [4] [5]; however, its transcriptional consequences have not been resolved. In part, this reflects uncertainty as to whether binding of SAPK/JNK inhibits c-Jun function directly [6] [7] or, alternatively, serves to facilitate and maintain the specificity of positive regulatory phosphorylation [8]. Using a two-hybrid approach, we show that SAPK/JNK stimulates c-Jun transactivation in yeast and that this depends on both catalytic activity and physical interaction between the kinase and its substrate. Furthermore, c-Jun is active when tethered to DNA via SAPK/JNK, demonstrating that kinase binding does not preclude transactivation. Taken together, these results suggest that SAPK/JNK acts primarily as a positive regulator of c-Jun transactivation in situ, and that loss of the docking site physically uncouples v-Jun from this control. This loss-of-function model accounts for the deficit of v-Jun regulatory phosphorylation and repression of TPA response element (TRE)-dependent transcription observed in v-Jun-transformed cells and predicts that an important property of the oncoprotein is to antagonise SAPK/JNK-dependent gene expression.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Kinases
/
Signal Transduction
/
Gene Expression Regulation
/
Oncogene Protein p65(gag-jun)
/
Mitogen-Activated Protein Kinases
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Curr Biol
Journal subject:
BIOLOGIA
Year:
1998
Document type:
Article
Affiliation country:
United kingdom