Prevention of CCAAT/enhancer-binding protein β DNA binding by hypoxia during adipogenesis

Young Kwon Park, Hyunsung Park

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Upon exposure to adipogenesis-inducing hormones, confluent 3T3-L1 preadipocytes express C/EBPβ (CCAAT/enhancer binding protein β). Early induced C/EBPβ is inactive but, after a lag period, acquires its DNA-binding capability by sequential phosphorylation. During this period, preadipocytes pass the. G1/S checkpoint synchronously. Thr 188 of C/EBPβ is phosphorylated initially to prime the factor for subsequent phosphorylation at Ser184 or Thr179 by GSK3β, which translocates into the nuclei during the G1/S transition. Many events take place during the G1/S transition, including reduction in p27Kip1 protein levels, retinoblastoma (Rb) phosphorylation, GSK3β nuclear translocation, and C/EBPβ binding to target promoters. During hypoxia, hypoxia-inducible factor-1α(HIF- 1α) is stabilized, thus maintaining expression of p27Kip1, which inhibits Rb phosphorylation. Even under normoxic conditions, constitutive expression of p27Kip1 blocks the nuclear translocation of GSK3β and DNA binding capability of C/EBPβ. Hypoxia also blocks nuclear translocation of GSK3β and DNA binding capability of C/EBPβ in HIF-1α knockdown 3T3-L1 cells that fail to induce p27Kip1. Nonetheless, under hypoxia, these cells can block Rb phosphorylation and theG1/S transition. Altogether, these findings suggest that hypoxia prevents the nuclear translocation of GSK3β and the DNA binding capability of C/EBPβ by blocking the G 1/S transition through HIF-1α-dependent induction of p27 Kip1 and an HIF-1α/p27-independent mechanism.

Original languageEnglish
Pages (from-to)3289-3299
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number5
DOIs
StatePublished - 29 Jan 2010

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