CCAAT/enhancer binding protein α (C/EBPα) and C/EBPα myeloid oncoproteins induce Bcl-2 via interaction of their basic regions with nuclear factor-κB p50

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Abstract

The CEBPA gene is mutated in 10% of acute myeloid leukemia (AML) cases. We find that CEBPA and Bcl-2 RNA levels correlate highly in low-risk human AMLs, suggesting that inhibition of apoptosis via induction of bcl-2 by CCAAT/enhancer binding protein α (C/EBPα) or its mutant variants contributes to transformation. C/EBPαp30, lacking a NH2-terminal transactivation domain, or C/EBPαLZ, carrying in-frame mutations in the leucine zipper that prevent DNA binding, induced bcl-2 in hematopoietic cell lines, and C/EBPα induced bcl-2 in normal murine myeloid progenitors and in the splenocytes of H2K-C/EBPα-Eμ transgenic mice. C/EBPα protected Ba/F3 cells from apoptosis on interleukin-3 withdrawal but not if bcl-2 was knocked down. Remarkably, C/EBPαLZ oncoproteins activated the bcl-2 P2 promoter despite lack of DNA binding, and C/EBPαp30 also activated the promoter. C/EBPα and the C/EBPα oncoproteins cooperated with nuclear factor-κB (NF-κB) p50, but not p65, to induce bcl-2 transcription. Endogenous C/EBPα preferentially coimmunoprecipitated with p50 versus p65 in myeloid cell extracts. Mutation of residues 297 to 302 in the C/EBPα basic region prevented induction of endogenous bcl-2 or the bcl-2 promoter and interaction with p50 but not p65. These findings suggest that C/EBPα or its mutant variants tether to a subset of NF-κB target genes, including Bcl-2, via p50 to facilitate gene activation and offer an explanation for preferential in-frame rather than out-of-frame mutation of the leucine zipper with sparing of the basic region in C/EBPαLZ oncoproteins. Targeting interaction between C/EBPα basic region and NF-κB p50 may contribute to the therapy of AML and other malignancies expressing C/EBPs. Copyright © 2005 American Association for Cancer Research.

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Paz-Priel, I., Cai, D. H., Wang, D., Kowalski, J., Blackford, A., Liu, H., … Friedman, A. D. (2005). CCAAT/enhancer binding protein α (C/EBPα) and C/EBPα myeloid oncoproteins induce Bcl-2 via interaction of their basic regions with nuclear factor-κB p50. Molecular Cancer Research, 3(10), 585–596. https://doi.org/10.1158/1541-7786.MCR-05-0111

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