Hypoxia inducible factor-1α regulates autophagy via the p27-E2F1 signaling pathway.
Hypoxia inducible factor-1α regulates autophagy via the p27-E2F1 signaling pathway.
复制标题
缺氧诱导因子 1 α 通过 p27-E2F1 信号通路调节自噬
DOI：
10.3892/mmr.2017.6794
复制
发表时间：
2017-08
影响因子：
3.4
通讯作者：
Ming L
中科院分区：
文献类型：
--
作者：
Wang P;Long M;Zhang S;Cheng Z;Zhao X;He F;Liu H;Ming L
自噬是一种高度保守的过程，通过这种过程，细胞内容物被运送到溶酶体进行降解，或者在营养饥饿的条件下用于提供能量产生的大分子。以往的研究表明，低氧区的癌细胞在氧浓度低于正常生理水平的情况下，为了适应和生存，会表达缺氧诱导因子-1α。低氧诱导因子-1α在氧稳态的调节中起重要作用，在低氧条件下转录成百上千个基因，从而维持能量和氧化还原稳态。为了确定低氧诱导因子-1α是否调节自噬及其调控这一过程的潜在分子机制，将人食道癌EC109和IMR90人二倍体成纤维细胞系暴露于常氧和低氧条件下，并随后检测各种蛋白的表达水平。用小干扰RNA沉默p27，以探讨其在HIF-1α调控自噬过程中的作用。低氧诱导IMR90细胞自噬，未成熟的IMR90细胞表现出比成熟细胞更高的自噬。HIF-1α通过正向调节p27促进EC109细胞自噬，而沉默p27则抑制缺氧诱导的自噬。本研究确定了p27-E2F1信号通路的主要组成部分，缺氧诱导因子-1α通过该信号通路调节自噬。这里提出了一种以前未知的机制，通过这种机制，癌细胞可以产生能量，或获得生存所需的大分子。
Autophagy is a highly conserved process by which the cell contents are delivered to lysosomes for degradation, or are used to provide macromolecules for energy generation under conditions of nutritional starvation. It has previously been demonstrated that cancer cells in hypoxic regions, with an oxygen concentration below the normal physiological level, express hypoxia inducible factor (HIF)-1α, in order to adapt and survive. HIF-1α is important in the regulation of oxygen homeostasis and the transcription of hundreds of genes in response to conditions of hypoxia, hence maintaining energy and redox homeostasis. To determine if HIF-1α modulates autophagy and the underlying molecular mechanisms regulating this process, the human esophageal cancer EC109 and IMR90 human diploid fibroblast cell lines were exposed to normoxic or hypoxic conditions and the expression levels of various proteins subsequently examined. Small interfering RNA was used to silence p27, in order to investigate its role in the process of HIF-1α regulated autophagy. Hypoxia induced autophagy in IMR90 cells and it was revealed that immature IMR90 cells demonstrated an increased rate of autophagy compared with mature cells. HIF-1α promoted EC109 cell autophagy via positively modulating p27, whereas silencing of p27 abolished the autophagy induced by hypoxia. The present study identified the primary components of the p27-E2F1 signaling pathway by which HIF-1α regulates autophagy. A previously unidentified mechanism is here presented, via which cancer cells may generate energy, or obtain macromolecules for survival.
登录
查看更多内容
DOI：
10.1038/nrc3262
发表时间：
2012-04-26
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.5
作者：
Kirschner K;Samarajiwa SA;Cairns JM;Menon S;Pérez-Mancera PA;Tomimatsu K;Bermejo-Rodriguez C;Ito Y;Chandra T;Narita M;Lyons SK;Lynch AG;Kimura H;Ohbayashi T;Tavaré S;Narita M
通讯作者：
Narita M
影响因子：
11.2
作者：
Jiang H;Martin V;Gomez-Manzano C;Johnson DG;Alonso M;White E;Xu J;McDonnell TJ;Shinojima N;Fueyo J
通讯作者：
Fueyo J
影响因子：
6.6
作者：
Cao, Ji;Ying, Meidan;Yang, Bo
通讯作者：
Yang, Bo
影响因子：
8
作者：
Unruh, A;Ressel, A;Wenger, RH
通讯作者：
Wenger, RH