Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Torrance, California 90502.
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Torrance, California 90502.
J Biol Chem. 2010 Mar 26;285(13):9373-9382. doi: 10.1074/jbc.M109.094425. Epub 2010 Jan 28.
CCCTC binding factor (CTCF) controls DNA imprinting, insulates important gene expression, and mediates growth factor- and stress-induced cell fate. However, regulatory mechanisms involved in intracellular CTCF activity are largely unknown. In this study, we show that epidermal growth factor (EGF)-induced increase and UV stress-induced decrease in CTCF activities mediate human corneal epithelial cell proliferation and apoptosis, respectively. CTCF is regulated by activation of different NF-kappaB subtypes via stimulation by EGF and UV stress. EGF-induced formation of a p65/p50 heterodimer activated CTCF transcription to promote cellular proliferation. This was accomplished by the heterodimer binding to a kappaB site in the promoter region of CTCF gene. In contrast, UV stress induced formation of a p50/p50 homodimer, which suppressed CTCF expression leading to apoptosis. Thus, CTCF by itself plays a central role in mediating the dichotomous effects of growth factor- and stress-stimulated NF-kappaB activation on cell survival and death. These results suggest that CTCF is a downstream component of the NF-kappaB pathway involved in the core transcriptional network of cell fate.
CCCTC 结合因子（CTCF）控制 DNA 印迹，隔离重要的基因表达，并介导生长因子和应激诱导的细胞命运。然而，细胞内 CTCF 活性的调节机制在很大程度上是未知的。在这项研究中，我们表明表皮生长因子（EGF）诱导的 CTCF 活性增加和 UV 应激诱导的 CTCF 活性降低分别介导人角膜上皮细胞的增殖和凋亡。CTCF 通过 EGF 和 UV 应激的刺激被不同的 NF-κB 亚型激活所调节。EGF 诱导的 p65/p50 异二聚体的形成激活了 CTCF 的转录，促进了细胞的增殖。这是通过异二聚体与 CTCF 基因启动子区域中的 kappaB 位点结合来实现的。相比之下，UV 应激诱导了 p50/p50 同源二聚体的形成，抑制了 CTCF 的表达，导致细胞凋亡。因此，CTCF 本身在介导生长因子和应激刺激的 NF-κB 激活对细胞存活和死亡的双重影响中起着核心作用。这些结果表明，CTCF 是 NF-κB 途径的下游成分，参与细胞命运的核心转录网络。
