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Hypoxia-induced adaptive responses.

机译：低氧诱导的适应性反应。

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摘要

Hypoxia is a physiological condition defined as the oxygen concentration is lower than 5% in general while normoxia is around 20%. It has been reported that hypoxia is related to numerous human diseases, such as respiratory diseases, vascular diseases, neurodegeneration and cancer, and hypoxic stress activates various signal transduction pathways to regulate cellular adaptive responses. Desferroxamine (DFO), a hypoxia-mimetic agent, functions as an iron chelator and has been utilized in hypoxic study. However, the molecular mechanisms underlying hypoxia- and/or DFO-induced adaptive responses are still unclear. In this report, I demonstrate that hypoxia and DFO induce a transient global SUMOylation to augment cell survival against acute hypoxic stress by strengthening passive barrier properties, facilitating the reassembly of F-actin/ZO-1, attenuating pro-apoptotic PKCd/Caspase-3 activation, inducing S1981 phosphorylation of ATM, and activating pro-survival NF-kappaB signaling pathways. Under prolonged hypoxic treatment, DFO induces nuclear translocation and proteolytic cleavage of PKCdelta and PKCdelta-dependent Caspase-3 activation to render a sustained DFO-elicited gamma-H2AX activation leading to apoptotic cell death. Intriguingly, PKCdelta plays a fine-tuning role in modulating DFO-induced Akt phosphorylation. Moreover, DFO-exposure also induces a PKCdelta-independent signaling and both PKCdelta-dependent and -independent pathways functionally cooperate to integrate pro-apoptotic/Caspase-3, pro-survival/Akt, and DNA damage-induced DNA repair/cell cycle regulation signalings. An accumulation of autophagosomes was observed during 2 to 4 h post-hypoxic treatment. Autophagy is a tightly orchestrated intracellular process and is essential for cell survival or death in response to stress conditions. DFO-treatment renders a rapid and transient phosphorylation at Y-64 and Y-155 of PKCdelta and conveys JNK1 Thr183/Tyr185-phosphorylation. Inhibition of PKCdelta by PKCdeltaKD or PKCdelta-knockout reduces DFO-induced changes in LC3-II levels. The requirement of PKCdelta is apparent for DFO-, but not starvation-, induced autophagy. Both JNK1 activation and release of Beclin-1, a key molecule in autophagic process, from inhibitory bcl-2 are PKCdelta-dependent. Significantly, inhibition of autophagy by 3-MA or Atg5-knockout presents a more prevalence in cell death while PKCdelta- or JNK1-deficient cells exhibit resistance to long-term DFO-treatment. In summary, acute hypoxia/DFO stress induces a transient activation of SUMOylation and autophagy to protect cells against hypoxic injury, while prolonged treatment induces PKCdelta proteolytic activation leading to apoptotic cell death.
机译：缺氧是一种生理状况，定义为氧浓度通常低于5％，而常氧约为20％。据报道，缺氧与多种人类疾病有关，例如呼吸系统疾病，血管疾病，神经退行性疾病和癌症，并且低氧应激激活各种信号转导途径来调节细胞适应性反应。降铁胺（DFO），一种低氧模拟药，起铁螯合剂的作用，已被用于低氧研究。但是，低氧和/或DFO诱导的适应性反应的分子机制仍不清楚。在本报告中，我证明了低氧和DFO可以通过增强被动屏障特性，促进F-actin / ZO-1的重组，减弱促凋亡的PKCd / Caspase-3来诱导短暂的全局SUMOylation，从而增强针对急性低氧应激的细胞存活率。激活，诱导ATM的S1981磷酸化，并激活生存前的NF-κB信号通路。在长时间的缺氧治疗下，DFO诱导PKCdelta和PKCdelta依赖的Caspase-3活化的核易位和蛋白水解切割，从而导致DFO引起的持续γ-H2AX活化，从而导致凋亡性细胞死亡。有趣的是，PKCdelta在调节DFO诱导的Akt磷酸化中起微调作用。此外，DFO暴露还诱导了PKCdelta独立的信号传导，并且PKCdelta独立和独立的途径在功能上协同整合了促凋亡/ Caspase-3，促存活/ Akt和DNA损伤诱导的DNA修复/细胞周期调控信号。缺氧后2至4小时内观察到自噬体的积累。自噬是紧密协调的细胞内过程，对于应激条件下的细胞存活或死亡至关重要。 DFO处理使PKCdelta的Y-64和Y-155发生快速且短暂的磷酸化，并传递JNK1 Thr183 / Tyr185磷酸化。 PKCdeltaKD或PKCdelta敲除对PKCdelta的抑制作用可降低DFO诱导的LC3-II水平的变化。 PKCdelta的需求对于DFO-（而非饥饿）诱导的自噬很明显。 JNK1激活和自噬过程中的关键分子Beclin-1从抑制性bcl-2释放都是PKCdelta依赖性的。值得注意的是，3-MA或Atg5-敲除对自噬的抑制作用在细胞死亡中更为普遍，而PKCdelta或JNK1缺失的细胞则表现出对长期DFO处理的抵抗力。总之，急性缺氧/ DFO应激会诱导SUMOylation和自噬的短暂激活，以保护细胞免受低氧损伤，而长期治疗会诱导PKCdelta蛋白水解激活，从而导致凋亡的细胞死亡。

著录项

  • 作者

    Chen, Jo-Lin.;

  • 作者单位

    University of Southern California.;

  • 授予单位 University of Southern California.;
  • 学科 Biology Molecular.;Health Sciences Toxicology.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 140 p.
  • 总页数 140
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;药理学;毒物学（毒理学）;
  • 关键词

  • 入库时间 2022-08-17 11:39:00

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