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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Egr1 mediates p53-independent c-Myc-induced apoptosis via a noncanonical ARF-dependent transcriptional mechanism
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Egr1 mediates p53-independent c-Myc-induced apoptosis via a noncanonical ARF-dependent transcriptional mechanism

机译：Egr1通过非规范的ARF依赖转录机制介导p53独立的c-Myc诱导的细胞凋亡。

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摘要

c-Myc is frequently deregulated in human cancers. Although deregulated c-Myc leads to tumor growth, it also triggers apoptosis in partnership with tumor suppressors such as ARF and p53. Apoptosis induced by c-Myc is a critical fail-safe mechanism for the cell to protect against unrestrained proliferation. Despite the plethora of information on c-Myc, the molecular mechanism of how c-Myc induces both transformation and apoptosis is unclear. Oncogenic c-Myc can indirectly induce the expression of the tumor suppressor ARF, which leads to apoptosis through the stabilization of p53, but both c-Myc and ARF have apoptotic activities that are independent of p53. In cells without p53, ARF directly binds to c-Myc protein and inhibits c-Myc-induced hyperproliferation and transformation with a concomitant inhibition of canonical c-Myc target gene induction. However, ARF is an essential cofactor for p53-independent c-Myc-induced apoptosis. Here we show that ARF is necessary for c-Myc to drive transcription of a unique non-canonical target gene, Egr1. In contrast, c-Myc induces another family member, Egr2, through a canonical mechanism that is inhibited by ARF. We further demonstrate that Egr1 is essential for p53-independent c-Myc-induced apoptosis, but not ARF-independent c-Myc-induced apoptosis. Therefore, ARF binding switches the inherent activity of c-Myc from a proliferative to apoptotic protein without p53 through a unique noncanonical transcriptional mechanism. These findings also provide evidence that cofactors can differentially regulate specific transcriptional programs of c-Myc leading to different biological outcomes.
机译：c-Myc在人类癌症中经常被放松调节。尽管失调的c-Myc导致肿瘤生长，但它也与肿瘤抑制因子（如ARF和p53）一起触发凋亡。 c-Myc诱导的细胞凋亡是细胞保护细胞免受不受限制的增殖的关键故障安全机制。尽管有大量有关c-Myc的信息，但尚不清楚c-Myc如何诱导转化和凋亡的分子机制。致癌c-Myc可以间接诱导肿瘤抑制因子ARF的表达，从而通过稳定p53导致细胞凋亡，但c-Myc和ARF均具有独立于p53的凋亡活性。在没有p53的细胞中，ARF直接与c-Myc蛋白结合并抑制c-Myc诱导的过度增殖和转化，并伴有对典型c-Myc靶基因诱导的抑制作用。但是，ARF是独立于p53的c-Myc诱导的细胞凋亡的重要辅助因子。在这里，我们显示ARF对于c-Myc驱动独特的非经典靶基因Egr1的转录是必需的。相反，c-Myc通过被ARF抑制的典型机制诱导另一个家族成员Egr2。我们进一步证明，Egr1对于p53独立的c-Myc诱导的细胞凋亡是必不可少的，而不是ARF独立的c-Myc诱导的细胞凋亡。因此，ARF结合通过独特的非规范转录机制将c-Myc的固有活性从无p53的增殖性蛋白转换为凋亡蛋白。这些发现还提供了辅助因子可以差异调节c-Myc特定转录程序从而导致不同生物学结果的证据。

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  • 作者

    David N. Boone; Ying Qi; Zhaoliang Li; Stephen R. Harm;

  • 作者单位

    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-2175;

    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-2175;

    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-2175;

    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-2175;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    oncogene; cell death;

    机译：癌基因细胞死亡;

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