NOVEL MECHANISM OF C/EBP-BETA (NF-M) TRANSCRIPTIONAL CONTROL - ACTIVATION THROUGH DEREPRESSION
NOVEL MECHANISM OF C/EBP-BETA (NF-M) TRANSCRIPTIONAL CONTROL - ACTIVATION THROUGH DEREPRESSION
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DOI：
10.1101/gad.8.22.2781
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发表时间：
1994-11-15
影响因子：
10.5
通讯作者：
LEUTZ, A
中科院分区：
文献类型：
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作者：
KOWENZLEUTZ, E;TWAMLEY, G;LEUTZ, A
转录因子的磷酸化被认为是控制其在基因表达调控中活性的主要机制。C/EBPβ是一种转录因子，在磷酸化后被激活，诱导参与炎症、急性时相反应、细胞因子表达、细胞生长和分化的基因。鸡的同源核因子-M与Myb和各种激酶癌基因在正常的髓系分化以及粒单核细胞的白血病转化中协同工作。在这里，我们研究了核因子-M的结构及其激活机制。我们发现，核因子-M是一种被抑制的转录因子，具有潜在的激活潜能。在报告实验中，去抑制的核因子-M表现出增强的转录效率。更重要的是，即使在成纤维细胞或红细胞等异种细胞中，核因子-M也能激活固定的染色质嵌入的、单核细胞特异的靶基因。我们在核因子-M中发现了两个抑制反式激活的区域。这些区域的缺失、包括v-erbB、多瘤中T、ras和mIL/RAF在内的信号转导激酶的激活，或者MAP激酶关键的磷酸化位点的点突变，都可以取消抑制。我们提供的证据表明，作为一种通过核因子-M/C/EBPβ调节基因表达的新机制，磷酸化在下调而不是增强反式激活结构域方面发挥着独特的作用。
Phosphorylation of transcription factors is regarded as a major mechanism to control their activity in regulation of gene expression. C/EBP beta is a transcription factor that becomes activated after phosphorylation to induce genes involved in inflammation, acute-phase response, cytokine expression, cell growth, and differentiation. The chicken homolog NF-M collaborates with Myb and various kinase oncogenes in normal myeloid differentiation as well as in the leukemic transformation of myelomonocytic cells. Here, we examined the structure of NF-M and its mechanism of activation. We show that NF-M is a repressed transcription factor with concealed activation potential. Derepressed NF-M exhibits enhanced transcriptional efficacy in reporter assays. More importantly, NF-M activates resident chromatin-embedded, myelomonocyte-specific target genes, even in heterologous cell types such as fibroblasts or erythroblasts. We identified two regions within NF-M that act to repress trans-activation. Repression is abolished by deletion of these regions, activation of signal transduction kinases including v-erbB, polyoma middle T, ras and mil/raf, or point mutation of a critical phosphorylation site for MAP kinases. We provide evidence that phosphorylation plays a unique role to derepress rather than to enhance the trans-activation domain as a novel mechanism to regulate gene expression by NF-M/C/EBP beta.