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首页> 外文学位 >Investigation of poly(ADP-ribose) glycohydrolase (PARG) in cancer: Discovery of novel targets to improve chemotherapy.
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Investigation of poly(ADP-ribose) glycohydrolase (PARG) in cancer: Discovery of novel targets to improve chemotherapy.

机译：聚（ADP-核糖）糖水解酶（PARG）在癌症中的研究：发现改善化疗的新目标。

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摘要

Poly(ADP-ribose) glycohydrolase (PARG) is the primary enzyme that catalyzes the hydrolysis of poly(ADP-ribose) (PAR), which is synthesized by poly(ADP-ribose) polymerases (PARPs) to modify cellular proteins. PARG participates in a number of biological processes, including chromatin dynamics, transcriptional regulation, DNA damage repair, and cell death. However, compared with the established chemotherapeutic potential of inhibiting PAR synthesis by targeting the PARPs, the significance of PARG as a therapeutic target in cancer remains to be elucidated.;The first chapter is a literature review of the current knowledge of PARG with a focus on its roles in DNA repair and cell death. In this section, the PAR mediated cell death pathway, Parthanatos, is introduced. Proteins that participate in this pathway including PARP-1, PARG, apoptosis-inducing factor (AIF) and the transient receptor potential, melastatin-2 (TRPM2) Ca 2+ channel are discussed.;To investigate their roles following DNA damage, we utilized genetic knockout, RNA interference or pharmacological inhibitors to silence PARG and other related proteins. We provide evidence that: 1) the absence of PAR hydrolysis due to the absence of PARG results in the vulnerability of DNA to damaging agents, decreased caspase activity and enhanced AIF mediated cell death; 2) inhibition of both PARP-1 and PARG does not lead to synergistic cell death; 3) silencing of AIF shows the ability of AIF to substitute as a primary mediator of breast cancer cell death in the absence of caspases; and 4) TRPM2 differentially regulates cell proliferation in non-cancerous versus cancerous cells. The inhibition of TRPM2 in breast cancer cells impaired cell growth and greatly enhanced cell death in the presence of chemotherapeutic agents.;Thus, by investigating the molecular mechanism of cell death mediated by PAR/PARG, we conclude that the induction of cell death mediated by AIF or specific targeting of TRPM2, has the great potential in chemotherapy to optimize the eradication of breast cancer cells.
机译：聚（ADP-核糖）糖水解酶（PARG）是催化聚（ADP-核糖）（PAR）水解的主要酶，该酶由聚（ADP-核糖）聚合酶（PARP）合成以修饰细胞蛋白。 PARG参与许多生物学过程，包括染色质动力学，转录调控，DNA损伤修复和细胞死亡。然而，与已确立的通过靶向PARPs抑制PAR合成的化学治疗潜力相比，PARG作为癌症治疗靶标的意义尚待阐明。第一章是对PARG当前知识的文献综述，重点是它在DNA修复和细胞死亡中的作用。在本节中，介绍了PAR介导的细胞死亡途径Parthanatos。讨论了参与该途径的蛋白质，包括PARP-1，PARG，凋亡诱导因子（AIF）和瞬时受体电位melastatin-2（TRPM2）Ca 2+通道。为了研究其在DNA损伤后的作用，我们利用了基因敲除，RNA干扰或药理抑制剂可使PARG和其他相关蛋白沉默。我们提供的证据是：1）由于不存在PARG而导致的PAR水解不存在导致DNA易受破坏剂破坏，胱天蛋白酶活性降低和AIF介导的细胞死亡增加； 2）抑制PARP-1和PARG均不会导致协同细胞死亡。 3）AIF沉默显示在没有胱天蛋白酶的情况下，AIF可以替代其作为乳腺癌细胞死亡的主要介质； 4）TRPM2差异性调节非癌细胞与癌细胞之间的细胞增殖。乳腺癌细胞中TRPM2的抑制会损害细胞生长并在存在化学治疗剂的情况下大大增加细胞死亡。因此，通过研究由PAR / PARG介导的细胞死亡的分子机制，我们得出结论，由PAR / PARG介导的细胞死亡的诱导AIF或TRPM2的特异性靶向在化学疗法中具有巨大潜力，可优化根除乳腺癌细胞。

著录项

  • 作者

    Feng, Xiaoxing.;

  • 作者单位

    Washington State University.;

  • 授予单位 Washington State University.;
  • 学科 Biology Molecular.;Health Sciences Pharmacy.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 194 p.
  • 总页数 194
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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