Downregulation of RUNX1 by RUNX3 Requires the RUNX3 VWRPY Sequence and Is Essential for Epstein-Barr Virus-Driven B-Cell Proliferation
Downregulation of RUNX1 by RUNX3 Requires the RUNX3 VWRPY Sequence and Is Essential for Epstein-Barr Virus-Driven B-Cell Proliferation
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DOI：
10.1128/jvi.00216-09
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发表时间：
2009-07-01
影响因子：
5.4
通讯作者：
Farrell, Paul J.
中科院分区：
文献类型：
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作者：
Brady, Gareth;Whiteman, Hannah J.;Farrell, Paul J.
RUNX 3对RUNX 1表达的交叉调节在调节感染EB病毒（EBV）的人B细胞的增殖中起关键作用。当EBV感染诱导RUNX 3时，随后的RUNX 1水平降低是随后的细胞增殖所必需的，因为在EBV淋巴母细胞样细胞系中RUNX 1的强制表达阻止了细胞增殖。来自急性B淋巴细胞白血病的TEL-RUNX 1融合基因保留了几乎所有的RUNX 1序列，但在相同的测定中不阻止B细胞增殖。发现B细胞成熟抗原（BCMA）由淋巴瘤细胞系中条件表达的RUNX 3诱导。染色质免疫沉淀试验证实，RUNX 3结合到RUNX 1启动子在淋巴母细胞样细胞系和伯基特淋巴瘤细胞系。发现来自RUNX 3的C末端的TLE结合VWRPY序列是B淋巴瘤细胞系中RUNX 1 P1启动子的阻遏所需的。B细胞系中的阻遏机制最可能涉及将辅阻遏物TLE 3或TLE 4募集到RUNX 1启动子。结果证明了RUNX 3介导的RUNX 1抑制对于EBV驱动的B细胞增殖的重要性，并鉴定了人RUNX家族蛋白之间的功能差异。
Cross-regulation of RUNX1 expression by RUNX3 plays a critical role in regulating proliferation of human B cells infected with Epstein-Barr virus (EBV). When EBV infection induces RUNX3, the consequent reduction in RUNX1 levels is required for the ensuing cell proliferation because forced expression of RUNX1 in an EBV lymphoblastoid cell line prevented cell proliferation. The TEL-RUNX1 fusion gene from acute B-lymphocytic leukemia retains almost all of the RUNX1 sequence but does not prevent B-cell proliferation in the same assay. B-cell maturation antigen (BCMA) was found to be induced by conditionally expressed RUNX3 in a lymphoma cell line. Chromatin immunoprecipitation assays confirmed that RUNX3 binds to the RUNX1 promoter in a lymphoblastoid cell line and a Burkitt's lymphoma cell line. The TLE binding VWRPY sequence from the C terminus of RUNX3 was found to be required for repression of the RUNX1 P1 promoter in a B-lymphoma cell line. The mechanism of repression in B-cell lines most likely involves recruitment of corepressor TLE3 or TLE4 to the RUNX1 promoter. The results demonstrate the importance of RUNX3-mediated repression of RUNX1 for EBV-driven B-cell proliferation and identify functional differences between human RUNX family proteins.