C/EBPβ:: a major PML-RARA-responsive gene in retinoic acid-induced differentiation of APL cells
C/EBPβ:: a major PML-RARA-responsive gene in retinoic acid-induced differentiation of APL cells
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DOI：
10.1093/emboj/cdg556
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发表时间：
2003-11-03
期刊：
影响因子：
11.4
通讯作者：
Tenen, DG
中科院分区：
文献类型：
--
作者：
Duprez, E;Wagner, K;Tenen, DG
在急性早幼粒细胞白血病 (APL) 中，t(15;17) 易位以全反式视黄酸 (ATRA) 响应方式诱导早幼粒细胞分化阶段的阻断。在这里，我们报告说，在用 ATRA 处理后，t(15;17) 细胞 (NB4) 显示出 C/EBP 家族成员 C/EBPbeta 的蛋白质水平和结合活性非常迅速增加，而在 ATRA 抗性 NB4 细胞系中未观察到这种情况。我们进一步提供证据表明，ATRA 仅在表达 PML-RARA（早幼粒细胞白血病-视黄酸受体 α）的细胞中介导 C/EBPbeta 的直接增加。此外，反式激活实验表明，PML-RARA融合蛋白，而非反式激活缺陷的PML-RARA突变体，强烈地反式激活C/EBPbeta启动子。这些结果表明 PML-RARA 介导 ATRA 诱导的 C/EBPbeta 表达。最后，我们证明了 C/EBPbeta 在粒细胞分化中的重要性。我们发现，C/EBPbeta 不仅可以独立于 ATRA 或其他细胞因子的添加而诱导非 APL 骨髓细胞系的粒细胞分化，而且在 ATRA 诱导的 APL 细胞分化过程中也需要 C/EBPbeta 的诱导。综上所述，C/EBPbeta 是 ATRA 依赖性 PML-RARA 靶基因，参与 ATRA 诱导的 APL 细胞分化。
In acute promyelocytic leukemia (APL), the translocation t(15;17) induces a block at the promyelocytic stage of differentiation in an all-trans-retinoic acid (ATRA)-responsive manner. Here we report that upon treatment with ATRA, t(15;17) cells (NB4) reveal a very rapid increase in protein level and binding activity of C/EBPbeta, a C/EBP family member, which was not observed in an ATRA-resistant NB4 cell line. We further provide evidence that ATRA mediates a direct increase of C/EBPbeta, only in PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha)-expressing cells. In addition, transactivation experiments indicate that the PML-RARA fusion protein, but not PML-RARA mutants defective in transactivation, strongly transactivates the C/EBPbeta promoter. These results suggest that PML-RARA mediates ATRA-induced C/EBPbeta expression. Finally, we demonstrate the importance of C/EBPbeta in granulocytic differentiation. We show that not only does C/EBPbeta induce granulocytic differentiation of non-APL myeloid cell lines independent of addition of ATRA or other cytokines, but also that C/EBPbeta induction is required during ATRA-induced differentiation of APL cells. Taken together, C/EBPbeta is an ATRA-dependent PML-RARA target gene involved in ATRA-induced differentiation of APL cells.