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The role of p53-independent apoptotic pathways in tumorigenesis.

机译:p53独立的凋亡途径在肿瘤发生中的作用。

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摘要

Apoptosis is a critical process for the maintenance of cellular homeostasis and prevention of cancer. BCL-2 family proteins play a central role in the regulation of apoptosis and modulate death signaling through mitochondrial pathway.{09}The strong impact of the BCL-2 family on tumor development is well illustrated by findings with baby mouse kidney epithelial (BMK) cells immortalized by E1A and dominant negative p53 (p53DD). Immortalized BMK (iBMK) cells from mice deficient for both BAX and BAK, or that overexpress BCL-2, readily form tumors in nude mice, whereas those retaining functional BAX and/or BAK do not, suggesting that a p53-independent, but BAX and BAK-dependent apoptotic pathway is implicated in tumor suppression. Hence, understanding the molecular events regulating this p53-independent apoptotic pathway may provide insights into tumorigenesis and reveal novel targets for effective therapeutic approaches to cancer treatment. We show that in epithelial cells, ischemic conditions in the tumor microenvironment cause induction of the BH3-only protein PUMA, and BAX-and BAK-mediated apoptosis that suppresses tumorigenesis independent of the RB and p53 pathways. Blockade of this p53-independent apoptotic pathway by either loss-of-function of BAX and BAK or gain-of-function of BCL-2 in vivo does not merely extend viability, but also allows survival of genetically unstable cells which may further promote tumor development. Furthermore, determining the mechanism of apoptosis induction by the chemotherapeutic drug paclitaxel revealed that BH3-only protein BIM suppressed tumorigenesis and was required for paclitaxel responsiveness.{09}The targeting of BIM for degradation in proteasomes by the H-ras/MAPK pathway was the molecular basis for paclitaxel resistance in tumors with activating mutations in RAS, and paclitaxel responsiveness was restored by joint administration of the proteasome inhibitor Velcade. Thus rational combinatorial chemotherapy using proteasome inhibitors to enhance chemosensitivity to paclitaxel in tumors where the H-ras/MAPK pathway is activated may be therapeutically beneficial, implying that relating tumor genotype to effective treatment regimens is essential for successful therapeutic outcome. Finally, studying the enhanced tumorigenesis of tumor derived cell lines (TDCLs) after in vivo selection showed that multiple capabilities may be selected for and cooperate with each other during tumorigenesis, revealing the complexity of cancer development.
机译:细胞凋亡是维持细胞稳态和预防癌症的关键过程。 BCL-2家族蛋白在细胞凋亡的调控和通过线粒体途径调节死亡信号中起着核心作用。{09} BCL-2家族对肿瘤发生的强大影响已通过婴儿小鼠肾脏上皮(BMK)的发现很好地说明。被E1A和显性阴性p53(p53DD)永生的细胞。来自缺乏BAX和BAK或过度表达BCL-2的小鼠的永生BMK(iBMK)细胞容易在裸鼠中形成肿瘤,而保留功能性BAX和/或BAK的人则不会形成肿瘤,这表明p53无关,但BAX BAK依赖的凋亡途径与肿瘤抑制有关。因此,了解调节这种不依赖p53的细胞凋亡途径的分子事件可能会提供有关肿瘤发生的见解,并揭示有效治疗癌症的新方法的靶标。我们显示,在上皮细胞中,肿瘤微环境中的缺血条件导致仅BH3蛋白PUMA的诱导,以及BAX和BAK介导的凋亡,可独立于RB和p53途径抑制肿瘤发生。在体内通过BAX和BAK的功能丧失或BCL-2的功能获得来阻断与p53无关的凋亡途径,不仅延长了生存能力,而且还使可能进一步促进肿瘤发展的遗传不稳定细胞得以存活发展。此外,确定化疗药物紫杉醇诱导凋亡的机制后发现,仅BH3蛋白BIM抑制了肿瘤发生,是紫杉醇响应性所必需的。{09}通过H-ras / MAPK途径将BIM靶向降解蛋白酶体是通过联合施用蛋白酶体抑制剂Velcade可恢复具有激活性RAS突变的肿瘤中紫杉醇耐药性的分子基础,并恢复紫杉醇的响应性。因此,在H-ras / MAPK途径被激活的肿瘤中使用蛋白酶体抑制剂进行合理的组合化学疗法以增强对紫杉醇的化学敏感性可能在治疗上是有益的,这意味着将肿瘤基因型与有效的治疗方案联系起来对于成功的治疗结果至关重要。最后,在体内选择后研究肿瘤衍生细胞系(TDCL)增强的肿瘤发生能力表明,在肿瘤发生过程中可能会选择多种功能并相互配合,从而揭示了癌症发展的复杂性。

著录项

  • 作者

    Tan, Tingting.;

  • 作者单位

    Rutgers The State University of New Jersey and University of Medicine and Dentistry of New Jersey.;

  • 授予单位 Rutgers The State University of New Jersey and University of Medicine and Dentistry of New Jersey.;
  • 学科 Biology Molecular.; Biology Cell.; Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 173 p.
  • 总页数 173
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;肿瘤学;
  • 关键词

  • 入库时间 2022-08-17 11:40:20

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