| First Author | Paz-Priel I | Year | 2011 |
| Journal | Blood | Volume | 117 |
| Issue | 15 | Pages | 4085-94 |
| PubMed ID | 21346255 | Mgi Jnum | J:172830 |
| Mgi Id | MGI:5009096 | Doi | 10.1182/blood-2010-07-294470 |
| Citation | Paz-Priel I, et al. (2011) C/EBPalpha and C/EBPalpha oncoproteins regulate nfkb1 and displace histone deacetylases from NF-kappaB p50 homodimers to induce NF-kappaB target genes. Blood 117(15):4085-94 |
| abstractText | Mutated CEBPA defines a subgroup of acute myeloid leukemia (AML). We have previously shown that C/EBPalpha or its AML mutants synergize with NF-kappaB 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/EBPalpha or C/EBPalpha 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/EBPalpha depends on 2 conserved kappaB sites in the nfkb1 promoter. C/EBPalpha did not induce p65 expression. Thus, C/EBPalpha and p50 reciprocally regulate each other's expression, establishing a positive feedback relationship. Although p50 homodimers inhibit transcription, C/EBPalpha and p50 synergistically activate antiapoptotic genes. ChIP analysis showed that C/EBPalpha 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/EBPalpha, its AML variants, or C/EBPbeta 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-kappaB dysregulation in leukemia, and that the C/EBPalpha:p50 complex is a potential therapeutic target. |
