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
| Autor: | H. Phillip Koeffler, Linda M. Boxer, Dong Hong Cai, Jeanne Kowalski, Adrian F. Gombart, Huaitian Liu, Caroline A. Heckman, Amanda L. Blackford, Ido Paz-Priel, Alan D. Friedman, Dehua Wang |
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| Rok vydání: | 2005 |
| Předmět: |
Adult
Transcriptional Activation Cancer Research Leucine zipper Mutant Apoptosis HL-60 Cells Mice Transgenic Biology Cell Line Mice Transactivation Transcription (biology) Enhancer binding CEBPA CCAAT-Enhancer-Binding Protein-alpha Animals Humans RNA Messenger Promoter Regions Genetic Molecular Biology Oncogene Proteins Mice Inbred BALB C Ccaat-enhancer-binding proteins NF-kappa B p50 Subunit Myeloid leukemia Hematopoietic Stem Cells Molecular biology Rats Leukemia Myeloid Acute Proto-Oncogene Proteins c-bcl-2 Oncology Cancer research |
| Zdroj: | Molecular Cancer Research. 3:585-596 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-05-0111 |
| Popis: | 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 alpha (C/EBPalpha) or its mutant variants contributes to transformation. C/EBPalphap30, lacking a NH2-terminal transactivation domain, or C/EBPalphaLZ, carrying in-frame mutations in the leucine zipper that prevent DNA binding, induced bcl-2 in hematopoietic cell lines, and C/EBPalpha induced bcl-2 in normal murine myeloid progenitors and in the splenocytes of H2K-C/EBPalpha-Emu transgenic mice. C/EBPalpha protected Ba/F3 cells from apoptosis on interleukin-3 withdrawal but not if bcl-2 was knocked down. Remarkably, C/EBPalphaLZ oncoproteins activated the bcl-2 P2 promoter despite lack of DNA binding, and C/EBPalphap30 also activated the promoter. C/EBPalpha and the C/EBPalpha oncoproteins cooperated with nuclear factor-kappaB (NF-kappaB) p50, but not p65, to induce bcl-2 transcription. Endogenous C/EBPalpha preferentially coimmunoprecipitated with p50 versus p65 in myeloid cell extracts. Mutation of residues 297 to 302 in the C/EBPalpha 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/EBPalpha or its mutant variants tether to a subset of NF-kappaB 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/EBPalphaLZ oncoproteins. Targeting interaction between C/EBPalpha basic region and NF-kappaB p50 may contribute to the therapy of AML and other malignancies expressing C/EBPs. |
| Databáze: | OpenAIRE |
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