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

Qi Qun Tang, Mads Grønborg, Haiyan Huang, Jae Woo Kim, Tamara C. Otto, Akhilesh Pandey, M. Daniel Lane

Research output: Contribution to journalArticle

234 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9766-9771
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number28
DOIs
StatePublished - Jul 12 2005

Keywords

  • 3T3-L1 preadipocyte
  • Cell cycle
  • Differentiation
  • Mitotic clonal expansion

ASJC Scopus subject areas

  • General

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