CTCF functions as a critical regulator of cell-cycle arrest and death after ligation of the B cell receptor on immature B cells
CTCF functions as a critical regulator of cell-cycle arrest and death after ligation of the B cell receptor on immature B cells
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DOI：
10.1073/pnas.0237127100
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发表时间：
2003-01-21
影响因子：
11.1
通讯作者：
Morse, HC
中科院分区：
文献类型：
--
作者：
Qi, CF;Martensson, A;Morse, HC
WEHI 231 B细胞淋巴瘤被用作通过克隆缺失的自身耐受的模型，因为B细胞受体（BCR）连接导致细胞凋亡。细胞死亡前有两个关键事件：MYC表达的早期上升和下降以及与p21、p27和p53表达增强相关的细胞周期停滞。CTCF是一种转录因子，被鉴定为MYC的阻遏物，最近显示可引起细胞生长抑制。目前的研究表明，WEHI 231以及正常未成熟B细胞的BCR连接大大增加了CTCF的表达，这与MYC的下调有关，随后是生长停滞和细胞死亡。在WEHI 231中CTCF的条件表达模拟了与活化细胞的BCR连接，显示抑制MYC的表达，增强p27、p21、p53和pj 9ARF的表达，以及抑制细胞生长和诱导凋亡。与CTCF在控制B细胞死亡中的中心作用一致，CTCF反义构建体在WEHI 231中的条件性表达导致与MYC表达增强相关的p27、p21、p53和p19（ARF）的抑制。WEHI 231中通过BCR连接激活内源性CTCF基因座也可通过其他三种途径模拟凋亡性死亡：抑制磷酸肌醇3-激酶或mTOR/FRAP信号级联反应和用转化生长因子（TGF）-β处理。BCR连接或TGF-β处理导致的CTCF快速激活被CD 40连接抑制。这些结果表明，CTCF是未成熟B细胞中不同死亡信号传导途径的共同决定因素。
The WEHI 231 B cell lymphoma is used as a model of self-tolerance by clonal deletion because B cell receptor (BCR) ligation results in apoptosis. Two critical events precede cell death: an early rise and fall in expression of MYC and cell-cycle arrest associated with enhanced expression of p21, p27, and p53. CTCF is a transcription factor identified as a repressor of MYC recently shown to cause cell growth inhibition. The present studies demonstrate that BCR ligation of WEHI 231 as well as of normal immature B cells greatly increased expression of CTCF in association with down-regulation of MYC followed by growth arrest and cell death. Conditional expression of CTCF in WEHI 231 mimicked BCR ligation with activated cells showing repressed expression of MYC, enhanced expression of p27, p21, p53, and pj9ARF, and inhibition of cell growth and induction of apoptosis. In keeping with a central role for CTCF in control of B cell death, conditional expression of a CTCF antisense construct in WEHI 231 resulted in inhibition of p27, p21, p53, and p19(ARF) in association with enhanced expression of MYC. Activation of the endogenous CTCF locus by BCR ligation was also mimicked by three other routes to apoptotic death in WEHI 231: inhibition of the phosphoinositide 3-kinase or mTOR/FRAP signaling cascades and treatment with transforming growth factor (TGF)-beta. Rapid activation of CTCF by BCR ligation or treatment with TGF-beta was suppressed by ligation of CD40. These results demonstrate that CTCF is a common determinant to different pathways of death signaling in immature B cells.