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
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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DOI：
10.1158/1541-7786.mcr-05-0111
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发表时间：
2005-10-01
影响因子：
5.2
通讯作者：
Friedman, AD
中科院分区：
文献类型：
--
作者：
Paz-Priel, I;Cai, DH;Friedman, AD
CEBPA基因在10%的急性髓性白血病（AML）病例中发生突变。我们发现CEBPA和Bcl-2 RNA水平在低风险的人类AMLs中高度相关，这表明CCAAT/增强子结合蛋白α (C/EBP α)或其突变变体通过诱导Bcl-2抑制细胞凋亡有助于转化。C/EBP α p30缺乏nh2末端反激活结构域，或C/EBP α LZ，在亮氨酸zipper中携带阻止DNA结合的框架内突变，在造血细胞系中诱导bcl-2， C/EBP α在正常小鼠髓系祖细胞和H2K-C/EBP α - e mu转基因小鼠的脾细胞中诱导bcl-2。C/EBP α在白细胞介素-3戒断时可保护Ba/F3细胞免于凋亡，但在bcl-2下调时则无保护作用。值得注意的是，C/EBP α LZ癌蛋白激活了bcl-2 P2启动子，尽管缺乏DNA结合，C/EBP α p30也激活了启动子。肿瘤蛋白C/EBP α和C/EBP α与核因子κ B (nf - κ B) p50而非p65共同诱导bcl-2转录。在髓细胞提取物中，内源性C/EBP α优先与p50和p65共免疫沉淀。C/EBP α基本区297 ~ 302残基突变可抑制内源性bcl-2或bcl-2启动子的诱导，也可抑制与p50而非p65的相互作用。这些发现表明，C/EBP α或其突变变体通过p50与NF-kappa B靶基因亚群（包括Bcl-2）连接，促进基因激活，并解释了C/EBP α LZ癌蛋白中亮氨酸拉链在框内而非框外优先突变，同时保留了基本区域。靶向C/EBP α基础区与NF-kappa bp50之间的相互作用可能有助于治疗AML和其他表达C/EBP的恶性肿瘤。
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/EBP alpha) or its mutant variants contributes to transformation. C/EBP alpha p30, lacking a NH2-terminal transactivation domain, or C/EBP alpha LZ, carrying in-frame mutations in the leucine zipper that prevent DNA binding, induced bcl-2 in hematopoietic cell lines, and C/EBP alpha induced bcl-2 in normal murine myeloid progenitors and in the splenocytes of H2K-C/EBP alpha-E mu transgenic mice. C/EBP alpha protected Ba/F3 cells from apoptosis on interleukin-3 withdrawal but not if bcl-2 was knocked down. Remarkably, C/EBP alpha LZ oncoproteins activated the bcl-2 P2 promoter despite lack of DNA binding, and C/EBP alpha p30 also activated the promoter. C/EBP alpha and the C/EBP alpha, oncoproteins cooperated with nuclear factor-kappa B (NF-kappa B) p50, but not p65, to induce bcl-2 transcription. Endogenous C/EBP alpha preferentially coimmunoprecipitated with p50 versus p65 in myeloid cell extracts. Mutation of residues 297 to 302 in the C/EBP alpha 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/EBP alpha or its mutant variants tether to a subset of NF-kappa B 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/EBP alpha LZ oncoproteins. Targeting interaction between C/EBP alpha basic region and NF-kappa B p50 may contribute to the therapy of AML and other malignancies expressing C/EBPs.