C/EBPA and C/EBPA oncoproteins regulate nfkb1 and displace histone deacetylases from NF-κB p50 homodimers to induce NF-κB target genes

Ido Paz-Priel, Simone Houng, Julia Dooher, Alan D. Friedman

Research output: Contribution to journalArticlepeer-review

Abstract

Mutated CEBPA defines a subgroup of acute myeloid leukemia (AML). We have previously shown that C/EBPα or its AML mutants synergize with NF-κB p50 to activate antiapoptotic genes, including BCL2 and FLIP. Furthermore, p50 binds and activates the CEBPA gene in myeloid cells. We now report that C/EBPα or C/EBPα leucine zipper AML mutants bind in vivo to the nfkb1 (p50) promoter and induce its expression even in the presence of cycloheximide. Induction of p50 by C/EBPα depends on 2 conserved κB sites in the nfkb1 promoter. C/EBPα did not induce p65 expression. Thus, C/EBPα and p50 reciprocally regulate each other's expression, establishing a positive feedback relationship. Although p50 homodimers inhibit transcription, C/EBPα and p50 synergistically activate antiapoptotic genes. ChIP analysis showed that C/EBPα diminishes the occupation of histone deacetylase 1 (HDAC1) or HDAC3 on the endogenous FLIP promoter but not in mice lacking p50. Coimmunoprecipitation confirmed that C/EBPα, its AML variants, or C/EBPβ disrupt interaction between p50 and HDACs dependent on the C/EBP basic region. These findings suggest that C/EBPs displace HDACs from p50 homodimers bound to antiapoptotic genes, contributing to NF-κB dysregulation in leukemia, and that the C/EBPα:p50 complex is a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)4085-4094
Number of pages10
JournalBlood
Volume117
Issue number15
DOIs
StatePublished - Apr 14 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'C/EBPA and C/EBPA oncoproteins regulate nfkb1 and displace histone deacetylases from NF-κB p50 homodimers to induce NF-κB target genes'. Together they form a unique fingerprint.

Cite this