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Sequential phosphorylation of CCAAT enhancer-binding protein beta by MAPK and glycogen synthase kinase 3 beta is required for adipogenesis

 Qi-Qun Tang  ;  Mads Grønborg  ;  M. Daniel Lane  ;  Akhilesh Pandey  ;  Tamara C. Otto  ;  Jae-Woo Kim  ;  Haiyan Huang 
 Proceedings of the National Academy of Sciences of the United States of America, Vol.102(28) : 9766-9771, 2005 
Journal Title
 Proceedings of the National Academy of Sciences of the United States of America 
Issue Date
3T3-L1 Cells ; Adipocytes/cytology* ; Adipocytes/metabolism ; Animals ; CCAAT-Enhancer-Binding Protein-beta/metabolism* ; Cell Differentiation/physiology* ; Cell Nucleus/metabolism ; Chromatin Immunoprecipitation ; Chromatography, Liquid ; Electrophoresis, Polyacrylamide Gel ; Glycogen Synthase Kinase 3/metabolism* ; Glycogen Synthase Kinase 3 beta ; Immunoblotting ; Isoelectric Focusing ; Mass Spectrometry ; Mice ; Mitogen-Activated Protein Kinases/metabolism* ; PPAR gamma/metabolism ; Phosphorylation ; Transcriptional Activation/physiology
3T3-L1 preadipocyte ; cell cycle ; differentiation ; mitotic clonal expansion
CCAAT enhancer-binding protein (C/EBP)β, C/EBPα, and peroxisome proliferator activated receptor (PPAR)γ act in a cascade where C/EBPβ activates expression of C/EBPα and PPARγ, which then function as pleiotropic activators of genes that produce the adipocyte phenotype. When growth-arrested 3T3-L1 preadipocytes are induced to differentiate, C/EBPβ is rapidly expressed but still lacks DNA-binding activity. After a long (14-hour) lag, glycogen synthase kinase 3β enters the nucleus, which correlates with hyperphosphorylation of C/EBPβ and acquisition of DNA-binding activity. Concurrently, 3T3-L1 preadipocytes synchronously enter S phase and undergo mitotic clonal expansion, a prerequisite for terminal differentiation. Ex vivo and in vitro experiments with C/EBPβ show that phosphorylation of Thr-188 by mitogen-activating protein kinase “primes” C/EBPβ for subsequent phosphorylation on Ser-184 and Thr-179 by glycogen synthase kinase 3β, acquisition of DNA-binding function, and transactivation of the C/EBPα and PPARγ genes. The delayed transactivation of the C/EBPα and PPARγ genes by C/EBPβ appears necessary to allow mitotic clonal expansion, which would otherwise be prevented, because C/EBPα and PPARγ are antimitotic.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jae Woo(김재우) ORCID logo https://orcid.org/0000-0001-5456-9495
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