Phosphorylation and ubiquitination of the transcription factor sterol regulatory element-binding protein-1 in response to DNA binding.

Members of the sterol regulatory element-binding protein (SREBP) family of transcription factors control cholesterol and lipid metabolism and play critical roles during adipocyte differentiation. The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase ...
kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding. DNA binding enhances the direct interaction between the C-terminal domain of SREBP1 and GSK-3beta. Accordingly, we demonstrate that GSK-3beta is recruited to the promoters of SREBP target genes in vivo. As a result of the phosphorylation of Thr426 and Ser430, the ubiquitin ligase Fbw7 is recruited to SREBP molecules associated with target promoters. Using a reconstituted ubiquitination system, we demonstrate that Fbw7-mediated ubiquitination of SREBP1 is dependent on its DNA binding activity. Thus, DNA binding could provide a mechanistic link between the phosphorylation, ubiquitination, and degradation of active transcription factors.
Mesh Terms:
Cell Line, Cell Nucleus, DNA, Glycogen Synthase Kinase 3, Hela Cells, Humans, Lipid Metabolism, Mutation, Phosphorylation, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Protein Binding, Sterol Regulatory Element Binding Protein 1, Ubiquitin
J. Biol. Chem.
Date: Sep. 01, 2006
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