C/EBPα:: AP-1 leucine zipper heterodimers bind novel DNA elements, activate the PU.1 promoter and direct monocyte lineage commitment more potently than C/EBPα homodimers or AP-1
C/EBPα:: AP-1 leucine zipper heterodimers bind novel DNA elements, activate the PU.1 promoter and direct monocyte lineage commitment more potently than C/EBPα homodimers or AP-1
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DOI：
10.1038/sj.onc.1210940
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发表时间：
2008-04-24
期刊：
影响因子：
8
通讯作者：
Friedman, A. D.
中科院分区：
文献类型：
--
作者：
Cai, D. H.;Wang, D.;Friedman, A. D.
碱性区亮氨酸拉链（BR-LZ或bZIP）转录因子通过其LZ结构域二聚化以定位相邻的BR用于DNA结合。C/EBP、AP-1和CREB/ATF bZIP亚家族的成员与相同子集的其他成员和结合特异性DNA基序形成同源二聚体或异源二聚体复合物。在这里，我们证明，C/EBP α也拉链AP-1蛋白，这种相互作用允许接触新的DNA元素和诱导的单核细胞谱系承诺在骨髓祖细胞。亮氨酸拉链交换：凝胶位移测定表明C/EBP α拉链与c-Jun、JunB或c-Fos，但不与c-Maf或MafB。为了评估特定同二聚体或异二聚体的活性，我们利用在其盐桥位置具有酸性（LZE）或碱性（LZK）残基的LZ。C/EBP α LZE：C/EBP alpha LZK优先结合C/EBP位点，c-JunLZE：c-FosLZK优先结合AP-1位点，C/EBP alpha LZE：c-JunLZK优先结合通过寡核苷酸选择鉴定为TTGCGTCAT的杂合元件。在鼠骨髓祖细胞中，C/EBP α：c-Jun或C/EBP α：c-Fos LZE：LZK异二聚体诱导单核细胞谱系定型，与C/EBP α或c-Jun同源二聚体或c-Jun：c-Fos异二聚体相比，其效力显著增加，证明了C/EBP：AP-1 bZIP亚家族相互作用的积极功能后果。C/EBP alpha：cJun结合并激活内源性PU.1启动子，提供了一种通过该复合物诱导单细胞生成的机制。
The basic-region leucine zipper (BR-LZ or bZIP) transcription factors dimerize via their LZ domains to position the adjacent BRs for DNA binding. Members of the C/EBP, AP-1 and CREB/ATF bZIP subfamilies form homodimeric or heterodimeric complexes with other members of the same subset and bind-specific DNA motifs. Here we demonstrate that C/EBP alpha also zippers with AP-1 proteins and that this interaction allows contact with novel DNA elements and induction of monocyte lineage commitment in myeloid progenitors. A leucine zipper swap: gel shift assay demonstrates that C/EBP alpha zippers with c-Jun, JunB or c-Fos, but not with c-Maf or MafB. To evaluate activities of specific homodimers or heterodimers we utilized LZs with acid (LZE) or basic (LZK) residues in their salt bridge positions. C/EBP alpha LZE: C/EBP alpha LZK preferentially binds a C/EBP site, c-JunLZE: c-FosLZK an AP-1 site and C/EBP alpha LZE: c-JunLZK a hybrid element identified as TTGCGTCAT by oligonucleotide selection. In murine myeloid progenitors, C/EBP alpha:c-Jun or C/EBP alpha:c-Fos LZE: LZK heterodimers induce monocyte lineage commitment with markedly increased potency compared with C/EBP alpha or c-Jun homodimers or c-Jun: c-Fos heterodimers, demonstrating a positive functional consequence of C/EBP: AP-1 bZIP subfamily interaction. C/EBP alpha:cJun binds and activates the endogenous PU.1 promoter, providing one mechanism for induction of monopoiesis by this complex.