GLUT4 enhancer factor (GEF) interacts with MEF2A and HDAC5 to regulate the GLUT4 promoter in adipocytes.
The insulin-responsive glucose transporter, GLUT4, is regulated in various physiologic states at the transcriptional level. When expressed in transgenic mice, the human GLUT4 promoter is governed by two cis-acting sequences: an MEF2 binding domain and Domain I, that function both as positive and negative regulators depending on the physiologic state. MEF2 proteins and GLUT4 enhancer factor (GEF) are known ligands for these cis-acting elements, but their mechanism of action is unclear. To begin to understand this important process, we have characterized GEF structural domains and its interactions with the MEF2A isoform. We find that the C terminus of GEF comprises its DNA-binding domain, but does not contribute to GEF homo-oligomerization. We also have found that GEF dimerizes with increased affinity to a hypophosphorylated form of MEF2A. Furthermore, we demonstrated that MEF2A binding to its cognate binding site can increase the DNA binding activity of GEF to Domain I, suggesting a novel mechanism for MEF2A transcriptional activation. Finally, we have demonstrated that the transcriptional co-repressor HDAC5 can interact with GEF in the absence of MEF2 proteins and specifically inhibit GLUT4 promoter activity. These findings lead to the hypothesis that GEF and the MEF2 proteins form a complex on the GLUT4 promoter that allows for recruitment of transcriptional co-regulators (repressors and/or activators) to control GLUT4 promoter activity.
Sparling
David P
DP
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190, USA.
Griesel
Beth A
BA
Weems
Juston
J
Olson
Ann Louise
AL
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C528734:GLUT4 enhancer factor, mouse; D051275:Glucose Transporter Type 4; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D018006:Myogenic Regulatory Factors; D020033:Protein Isoforms; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases