C/EBPalpha or C/EBPalpha oncoproteins regulate the intrinsic and extrinsic apoptotic pathways by direct interaction with NF-kappaB p50 bound to the bcl-2 and FLIP gene promoters.
C/EBPalpha or C/EBPalpha oncoproteins regulate the intrinsic and extrinsic apoptotic pathways by direct interaction with NF-kappaB p50 bound to the bcl-2 and FLIP gene promoters.
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CCAAT/增强子结合蛋白α（C/EBPα）在10%的急性髓性白血病中发生突变，导致蛋白质截短或亮氨酸拉链（C/EBPαLZ）改变，从而阻止DNA结合。C/EBPα协同NF-κB B p50诱导bcl-2抑制细胞凋亡。我们现在证明C/EBPα或C/EBPαLZ癌蛋白在染色质免疫沉淀试验中结合bcl-2 P2启动子，并依赖于κB位点的完整性诱导启动子。在B细胞中以转基因形式表达的C/EBPα结合并激活bcl-2启动子，但在缺乏NF-κB p50的nfkb 1 −/−小鼠中则不然。Bcl-2是内在凋亡途径的核心，而FLICE抑制蛋白（FLIP）调节caspase-8，启动caspase的外在途径。C/EBPα和C/EBPαLZ也结合FLIP启动子并诱导其依赖于NF-κB p50的表达。此外，C/EBPα诱导FLIP可保护脾细胞免受Fas配体诱导的凋亡，但仅在p50存在时。我们还证明了细菌产生的C/EBPα和NF-κB p50之间的直接相互作用，由C/EBPα碱性区域介导。这些发现表明，C/EBPα或其癌蛋白通过结合NF-κB p50与bcl-2和FLIP基因的启动子连接而激活bcl-2和FLIP基因。靶向它们的相互作用可能有利于转化细胞的凋亡。
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 NF-κB p50 to inhibit apoptosis. We now demostrate that C/EBPα or a C/EBPαLZ oncoprotein bind the bcl-2 P2 promoter in chromatin immunoprecipitation assays and induce 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, while 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 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 via bound NF-κB p50. Targeting their interaction may favor apoptosis of transformed cells.
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