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
Copyright policy )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
AbstractThe 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.
- National University of Singapore Singapore
- Stanford University United States
- Johns Hopkins University United States
- National University of Singapore Libraries Singapore
- University of California, Los Angeles United States
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protein p50, Apoptosis, animal cell, immunoprecipitation, Mice, gene mutation, Promoter Regions, Genetic, Oncogene Proteins, Mice, Inbred BALB C, adult, apoptosis, article, leucine zipper protein, acute granulocytic leukemia, gene induction, CCAAT enhancer binding protein alpha, Leukemia, Myeloid, Acute, immunoglobulin enhancer binding protein, oncoprotein, priority journal, Proto-Oncogene Proteins c-bcl-2, protein protein interaction, signal transduction, cell extract, myeloid progenitor cell, Adult, Transcriptional Activation, malignant transformation, protein bcl 2, cell protection, gene activation, animal experiment, embryo, 610, CEBPA gene, HL-60 Cells, Mice, Transgenic, protein DNA binding, hematopoietic cell, interleukin 3, animal tissue, Cell Line, promoter region, CCAAT-Enhancer-Binding Protein-alpha, Animals, Humans, controlled study, human, RNA, Messenger, gene, mouse, nonhuman, animal model, human cell, genetic transcription, NF-kappa B p50 Subunit, drug targeting, Hematopoietic Stem Cells, human tissue, Rats, transgenic mouse, synaptotagmin, RNA, amino terminal sequence, spleen cell
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