C/EBPα or C/EBPα oncoproteins regulate the intrinsic and extrinsic apoptotic pathways by direct interaction with NF-κB p50 bound to the bcl-2 and FLIP gene promoters

I. Paz-Priel, A. K. Ghosal, J. Kowalski, A. D. Friedman

Research output: Contribution to journalArticle

Abstract

CCAAT/enhancer-binding protein α (C/EBPα) is mutated in 10% of acute myeloid leukemias, resulting in either a truncated protein or an altered leucine zipper (C/EBPαLZ) that prevents DNA binding. C/EBPα induces bcl-2 in cooperation with nuclear factor-κB (NF-κB) p50 to inhibit apoptosis. We now demonstrate that C/EBPα or a C/EBPαLZ oncoprotein binds the bcl-2 P2 promoter in chromatin immunoprecipitation assays and induces the promoter dependent on the integrity of a κB site. C/EBPα expressed as a transgene in B cells binds and activates the bcl-2 promoter, but not in nfkb1-/- mice lacking NF-κB p50. Bcl-2 is central to the intrinsic apoptotic pathway, whereas FLICE inhibitory protein (FLIP) modulates caspase-8, the initiator caspase of the extrinsic pathway. C/ EBPα and C/EBPαLZ also bind the FLIP promoter and induce its expression dependent upon NF-κB p50. Moreover, induction of FLIP by C/EBPα protects splenocytes from Fas ligand-induced apoptosis, but only if p50 is present. We also demonstrate the direct interaction between bacterially produced C/EBPα and NF-κB p50, mediated by the C/EBPα basic region. These findings indicate that C/EBPα or its oncoproteins activate the bcl-2 and FLIP genes by tethering to their promoters through bound NF-κB p50. Targeting their interaction may favor apoptosis of transformed cells.

Original languageEnglish (US)
Pages (from-to)365-374
Number of pages10
JournalLeukemia
Volume23
Issue number2
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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