Cell growth inhibition by the multifunctional multivalent zinc-finger factor CTCF.
Cell growth inhibition by the multifunctional multivalent zinc-finger factor CTCF.
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发表时间：
2001-08
期刊：
影响因子：
11.2
通讯作者：
J. Rasko;E. Klenova;J. Leon;G. Filippova;D. Loukinov;S. Vatolin;A. Robinson;Y. Hu;J. Ulmer;M. Ward;E. Pugacheva;P. Neiman;H. Morse;S. Collins;Victor V Lobanenkov
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文献类型：
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作者：
J. Rasko;E. Klenova;J. Leon;G. Filippova;D. Loukinov;S. Vatolin;A. Robinson;Y. Hu;J. Ulmer;M. Ward;E. Pugacheva;P. Neiman;H. Morse;S. Collins;Victor V Lobanenkov
11-锌指蛋白CCT结合因子（CTCF）采用不同的锌指组与不同的CTCF-靶序列（CTS）形成不同的复合物，所述CTCF-靶序列介导基因表达的抑制或激活以及酶应答基因沉默子和不同脊椎动物增强子阻断元件（染色质绝缘子）的产生。为了确定这些不同的影响如何在体内整合，我们设计了各种表达系统来研究CTCF对细胞生长的影响。在这里，我们表明，CTCF在许多类型的细胞异位表达抑制细胞克隆形成引起深刻的生长迟缓，而没有凋亡。在异步培养中，CTCF表达细胞的细胞周期特征保持不变，这表明在多个点上细胞周期的进展减慢。尽管条件诱导的CTCF导致S期阻滞，但CTCF也可以阻止细胞分裂。表达CTCF的活细胞可以维持数天而不分裂。虽然MYC是CTCF靶点，但CTCF对细胞生长的抑制作用不能仅归因于MYC的抑制，这表明参与生长调节回路的其他CTS驱动基因（如p19 ARF）可能有助于CTCF诱导的生长停滞。这些发现表明，CTCF可能在细胞周期内的多个步骤调节细胞周期进程，并增加了CTCF作为肿瘤抑制基因的功能的证据。
The 11-zinc finger protein CCTC-binding factor (CTCF) employs different sets of zinc fingers to form distinct complexes with varying CTCF- target sequences (CTSs) that mediate the repression or activation of gene expression and the creation of hormone-responsive gene silencers and of diverse vertebrate enhancer-blocking elements (chromatin insulators). To determine how these varying effects would integrate in vivo, we engineered a variety of expression systems to study effects of CTCF on cell growth. Here we show that ectopic expression of CTCF in many cell types inhibits cell clonogenicity by causing profound growth retardation without apoptosis. In asynchronous cultures, the cell-cycle profile of CTCF-expressing cells remained unaltered, which suggested that progression through the cycle was slowed at multiple points. Although conditionally induced CTCF caused the S-phase block, CTCF can also arrest cell division. Viable CTCF-expressing cells could be maintained without dividing for several days. While MYC is the well-characterized CTCF target, the inhibitory effects of CTCF on cell growth could not be ascribed solely to repression of MYC, suggesting that additional CTS-driven genes involved in growth-regulatory circuits, such as p19ARF, are likely to contribute to CTCF-induced growth arrest. These findings indicate that CTCF may regulate cell-cycle progression at multiple steps within the cycle, and add to the growing evidence for the function of CTCF as a tumor suppressor gene.