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Apoptosis

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

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.

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Acknowledgements

This research was supported by the Samuel Waxman Cancer Research Foundation and the Children's Cancer Foundation (ADF), the Alex's Lemonade Stand Foundation (IPP) and by NIH Grant R01 HL082948 (ADF).

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Correspondence to A D Friedman.

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Paz-Priel, I., Ghosal, A., Kowalski, J. et al. 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. Leukemia 23, 365–374 (2009). https://doi.org/10.1038/leu.2008.297

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Keywords

  • C/EBPα
  • NF-κB
  • bcl-2
  • FLIP
  • apoptosis

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