GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity.
The oncoprotein BCL-3 is a nuclear transcription factor that activates NF-kappaB target genes through formation of heterocomplexes with p50 or p52. BCL-3 is phosphorylated in vivo, but specific BCL-3 kinases have not been identified so far. In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with HDAC1, -3, and -6 and attenuates its oncogenicity by selectively controlling the expression of a subset of newly identified target genes such as SLPI and Cxcl1. Our results therefore suggest that constitutive BCL-3 phosphorylation by GSK3 regulates BCL-3 turnover and transcriptional activity.
Laboratory of Medical Chemistry and Human Genetics, Liège, Belgium.
Patrick
P
Viatour
Emmanuel
E
Dejardin
Michael
M
Warnier
Florence
F
Lair
Estefania
E
Claudio
Fabrice
F
Bureau
Jean-Christophe
JC
Marine
Marie-Paule
MP
Merville
Ulrich
U
Maurer
Douglas
D
Green
Jacques
J
Piette
Ulrich
U
Siebenlist
Vincent
V
Bours
Alain
A
Chariot
D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D018797:Cell Cycle Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; C111664:protein p52, mammalian; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases