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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >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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CTCF functions as a critical regulator of cell-cycle arrest and death after ligation of the B cell receptor on immature B cells.

机译：在未成熟的B细胞上连接B细胞受体后，CTCF成为细胞周期停滞和死亡的关键调节剂。

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摘要

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 p19(ARF), 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 mTORFRAP 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.
机译：WEHI 231 B细胞淋巴瘤通过克隆缺失被用作自我耐受的模型，因为B细胞受体（BCR）的连接会导致细胞凋亡。细胞死亡之前有两个关键事件：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，最近被证明可引起细胞生长抑制。本研究表明，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，并伴有MYC的下调，随后的生长停滞和细胞死亡。 WEHI 231中CTCF的条件表达模拟了BCR与活化细胞的连接，该细胞显示出MYC的表达受抑制，p27，p21，p53和p19（ARF）的表达增强，并抑制了细胞的生长和凋亡的诱导。与CTCF在控制B细胞死亡中的核心作用保持一致，WEHI 231中CTCF反义构建体的条件表达导致p27，p21，p53和p19（ARF）的抑制与MYC表达的增强有关。通过BCR连接激活内源性CTCF基因座也被WEHI 231中的其他三种凋亡死亡途径模仿：抑制磷酸肌醇3激酶或mTORFRAP信号级联反应以及用转化生长因子（TGF）-β治疗。通过CD40的连接抑制​​了BCR连接或TGF-β处理对CTCF的快速激活。这些结果表明，CTCF是未成熟B细胞中不同死亡信号通路的共同决定因素。

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