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论文题目: Activation of G0S2 is coordinated by recruitment of PML/RAR alpha and C/EBP epsilon to its promoter during ATRA-induced APL differentiation
英文论文题目: Activation of G0S2 is coordinated by recruitment of PML/RAR alpha and C/EBP epsilon to its promoter during ATRA-induced APL differentiation
第一作者: Zhang, F; Zhu, YL; Deng, WL; Zhu, J; Zhang, J
英文第一作者: Zhang, F; Zhu, YL; Deng, WL; Zhu, J; Zhang, J
联系作者: Zhang, J (reprint author), Shanghai Jiao Tong Univ, State Key Lab Med Genom, Ruijin Hosp, Shanghai Inst Hematol,Sch Med, 197 Ruijin Rd 2, Shanghai 200025, Peoples R China.
英文联系作者: Zhang, J (reprint author), Shanghai Jiao Tong Univ, State Key Lab Med Genom, Ruijin Hosp, Shanghai Inst Hematol,Sch Med, 197 Ruijin Rd 2, Shanghai 200025, Peoples R China.
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发表年度: 2017
卷: 101
期: 3
页码: 655-664
摘要: All-trans retinoic acid (ATRA) binds the promyelocytic leukemia/retinoic acid receptor (PML/RAR) fusion protein and is an effective oncogene-targeted therapy for acute promyelocytic leukemia (APL). However, the molecular basis of PML/RAR-mediated transcriptional control during ATRA-induced differentiation is unclear. Previous studies have shown that the PML/RAR fusion protein behaves as a type II nuclear receptor, binding to DNA regardless of ligand status. Here, we performed a series of chromatin immunoprecipitation (ChIP)-quantitative PCR (qPCR) experiments, demonstrating that there is an additional mode of action of PML/RAR, wherein PML/RAR does not bind DNA in the absence of ATRA but binds DNA and activates adjacent genes in the presence of ATRA. This mode of action is similar to that of a type I nuclear receptor and is highlighted by activation of G0/G1 switch gene 2 (G0S2) during ATRA-induced neutrophil differentiation of leukemia cell lines (NB4 and PR9) and primary human APL cells. C/EBP epsilon occupancy of the G0S2 promoter was elevated in parallel with recruitment of PML/RAR in ATRA-treated NB4, PR9, and primary APL cells. Furthermore, we verified that the p30 isoform of C/EBP epsilon is crucial for activation of G0S2 and that PML/RAR interacts physically and cooperates functionally with C/EBP epsilon to up-regulate G0S2. Our data not only demonstrate a new mode of action of PML/RAR but also suggest a novel model in which PML/RAR synergizes with C/EBP epsilon to reactivate the C/EBP epsilon target G0S2, thereby contributing to ATRA-mediated APL differentiation and potentially, clinical remission.
英文摘要: All-trans retinoic acid (ATRA) binds the promyelocytic leukemia/retinoic acid receptor (PML/RAR) fusion protein and is an effective oncogene-targeted therapy for acute promyelocytic leukemia (APL). However, the molecular basis of PML/RAR-mediated transcriptional control during ATRA-induced differentiation is unclear. Previous studies have shown that the PML/RAR fusion protein behaves as a type II nuclear receptor, binding to DNA regardless of ligand status. Here, we performed a series of chromatin immunoprecipitation (ChIP)-quantitative PCR (qPCR) experiments, demonstrating that there is an additional mode of action of PML/RAR, wherein PML/RAR does not bind DNA in the absence of ATRA but binds DNA and activates adjacent genes in the presence of ATRA. This mode of action is similar to that of a type I nuclear receptor and is highlighted by activation of G0/G1 switch gene 2 (G0S2) during ATRA-induced neutrophil differentiation of leukemia cell lines (NB4 and PR9) and primary human APL cells. C/EBP epsilon occupancy of the G0S2 promoter was elevated in parallel with recruitment of PML/RAR in ATRA-treated NB4, PR9, and primary APL cells. Furthermore, we verified that the p30 isoform of C/EBP epsilon is crucial for activation of G0S2 and that PML/RAR interacts physically and cooperates functionally with C/EBP epsilon to up-regulate G0S2. Our data not only demonstrate a new mode of action of PML/RAR but also suggest a novel model in which PML/RAR synergizes with C/EBP epsilon to reactivate the C/EBP epsilon target G0S2, thereby contributing to ATRA-mediated APL differentiation and potentially, clinical remission.
刊物名称: JOURNAL OF LEUKOCYTE BIOLOGY
英文刊物名称: JOURNAL OF LEUKOCYTE BIOLOGY
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学科: Cell Biology; Hematology; Immunology
英文学科: Cell Biology; Hematology; Immunology
影响因子: 4.018
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论文类别: Article
英文论文类别: Article
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