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DNA binding promotes the phosphorylation‐dependent ubiquitination and degradation of the transcription factor SREBP1
Author(s) -
Ericsson Johan
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a979-b
Subject(s) - sterol regulatory element binding protein , transcription factor , promoter , ubiquitin ligase , phosphorylation , ubiquitin , microbiology and biotechnology , chemistry , biology , biochemistry , gene , gene expression
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 GSK‐3β‐dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding. DNA binding enhances the interaction between the C‐terminal domain of SREBP1 and GSK‐3β. Accordingly, we demonstrate that GSK‐3β is recruited to the promoters of SREBP‐regulated genes in vivo. As a result of the phosphorylation of Thr426 and Ser430 in SREBP1, the ubiquitin ligase Fbw7 is recruited to SREBP1 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 novel mechanistic link between the phosphorylation, ubiquitination and degradation of active transcription factors. The mechanisms involved in this regulatory system will be discussed.