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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >p53-dependent regulation of autophagy protein LC3 supports cancer cell survival under prolonged starvation
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p53-dependent regulation of autophagy protein LC3 supports cancer cell survival under prolonged starvation

机译：p53依赖的自噬蛋白LC3调控在长期饥饿下支持癌细胞存活

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摘要

The p53 tumor suppressor is mutated in a high percentage of human tumors. However, many other tumors retain wild-type (wt) p53 expression, raising the intriguing possibility that they actually benefit from it. Recent studies imply a role for p53 in regulation of autophagy, a catabolic pathway by which eukaryotic cells degrade and recycle macromolecules and organelles, particularly under conditions of nutrient deprivation. Here, we show that, in many cell types, p53 confers increased survival in the face of chronic starvation. We implicate regulation of autophagy in this effect. In HCT116 human colorectal cancer cells exposed to prolonged nutrient deprivation, the endogenous wt p53 posttranscriptionally down-regulates LC3, a pivotal component of the autophagic machinery. This enables reduced, yet sustainable autophagic flux. Loss of p53 impairs autophagic flux and causes excessive LC3 accumulation upon starvation, culminating in apoptosis. Thus, p53 increases cell fitness by maintaining better autophagic homeosta-sis, adjusting the rate of autophagy to changing circumstances. We propose that some cancer cells retain wt p53 to benefit from the resultant increased fitness under limited nutrient supply.
机译：p53肿瘤抑制因子在高比例的人类肿瘤中发生突变。然而，许多其他肿瘤保留了野生型（wt）p53表达，这增加了它们从中真正受益的有趣可能性。最近的研究表明p53在自噬调节中的作用，自噬是真核细胞降解并循环利用大分子和细胞器的分解代谢途径，特别是在营养缺乏的情况下。在这里，我们表明，在许多细胞类型中，面对慢性饥饿，p53可以提高生存率。我们暗示了自噬的调节作用。在暴露于长期营养剥夺的HCT116人类结直肠癌细胞中，内源性wt p53转录后下调LC3，这是自噬机制的关键组成部分。这样可以减少但可持续的自噬通量。 p53的丧失会损害自噬通量，并在饥饿时导致过多的LC3积累，最终导致细胞凋亡。因此，p53通过维持更好的自噬体内平衡，调节自噬速率以适应不断变化的环境来提高细胞适应性。我们建议一些癌细胞保留wt p53，以从有限养分供应下增加的适应性中受益。

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  • 作者

    Ruth Scherz-Shouval; Hilla Weidberg; Chagay Gonen; Sylvia Wilder; Zvulun Elazar; Moshe Oren;

  • 作者单位

    Departments of Molecular Cell Biology The Weizmann Institute of Science, Rehovot 76100, Israel;

    rnDepartments of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel;

    rnDepartments of Molecular Cell Biology The Weizmann Institute of Science, Rehovot 76100, Israel;

    rnDepartments of Molecular Cell Biology The Weizmann Institute of Science, Rehovot 76100, Israel;

    rnDepartments of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel;

    rnDepartments of Molecular Cell Biology The Weizmann Institute of Science, Rehovot 76100, Israel;

  • 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

    apoptosis; posttranscriptional regulation;

    机译：细胞凋亡转录后调控;

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