Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 35, Pages 25278-25286Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M604983200
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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 Thr(426) and Ser(430) in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3 beta-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-3 beta. Accordingly, we demonstrate that GSK-3 beta is recruited to the promoters of SREBP target genes in vivo. As a result of the phosphorylation of Thr(426) and Ser(430), 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.
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