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cIAP2 negatively regulates proliferation and tumourigenesis by repressing IKK activity and maintaining p53 function.

机译：cIAP2通过抑制IKK活性并维持p53功能来负调控增殖和肿瘤发生。

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摘要

The cellular inhibitor of apoptosis protein (cIAP)-2 plays an important role in the protection against apoptosis by inhibiting the endogenous IAP inhibitor Smac, thus allowing other members of the IAP family, such as XIAP to block caspases. Additionally, cIAP2 functions as a ubiquitin ligase and mediates survival/proliferative signaling through NF-κB. cIAP2 is overexpressed in many human cancers and is believed to play an oncogenic role. This led to the development of small molecule IAP antagonists aimed at eliciting apoptosis in cancer cells. However, the loss of cIAP2 is also associated with multiple myeloma, in which constitutively active NF-κB signaling contributes to pathogenesis of the disease and suggests that cIAP2 may also perform a tumour suppressive function.;We demonstrate a novel role for cIAP2 in maintaining p53 levels in mammary epithelial cells that express wildtype p53. Downregulation of cIAP2 resulted in activation of IKKs, which led to increased Mdm2-mediated degradation of p53. cIAP2 depletion also led to increased phosphorylation of ERK1/2. Reduction of p53 levels, in combination with survival signaling provided by NF-κB and MEK-ERK pathways were associated with increased colony formation in vitro and increased DMBA-induced adenocarcinomas in cIAP2-null mice.;Treatment of cells with IAP antagonists resulted in significant cytotoxicity only in p53-mutant MDA-MB-231 cells, which was associated with autocrine production of TNF-α. We propose that the transcription of TNF-α is potentiated by gain-of-function mutation in p53 since downregulation of mutant p53 in MDA-MB-231 cells decreased TNF-α mRNA. Downregulation of cIAPs in p53-mutant cells resulted in a decrease in nuclear IKK-α, which may result in decreased IKK-α-mediated survival signaling. In contrast, cIAP downregulation in p53-wildtype cells resulted in no change in nuclear IKK-α, degradation of the corepressor SMRT and cell survival. We show that the effects of cIAP2 downregulation are context-dependent. Downregulation of cIAP2 in p53-wildtype cells results in a decrease in p53 and an increase in survival and proliferative signaling. These results suggest a tumour suppressor function for cIAPs that may account for cIAP mutation-associated cancers such as multiple myeloma. Moreover, our data also defines gain-of-function p53 mutation as a possible contributor to IAP antagonist sensitivity.
机译：凋亡蛋白（cIAP）-2的细胞抑制剂通过抑制内源性IAP抑制剂Smac在保护细胞凋亡中发挥重要作用，从而使IAP家族的其他成员（例如XIAP）能够阻断胱天蛋白酶。另外，cIAP2发挥泛素连接酶的作用，并通过NF-κB介导生存/增殖信号传导。 cIAP2在许多人类癌症中均过表达，并被认为具有致癌作用。这导致了旨在引发癌细胞凋亡的小分子IAP拮抗剂的发展。然而，cIAP2的缺失也与多发性骨髓瘤有关，其中组成性活性NF-κB信号传导有助于该疾病的发病，并提示cIAP2可能还具有抑制肿瘤的功能。表达野生型p53的乳腺上皮细胞中的蛋白水平cIAP2的下调导致IKK激活，从而导致Mdm2介导的p53降解增加。 cIAP2消耗也导致ERK1 / 2磷酸化增加。降低p53水平，并结合NF-κB和MEK-ERK途径提供的生存信号与cIAP2空小鼠体外集落形成增加和DMBA诱导的腺癌增加有关。用IAP拮抗剂处理细胞导致显着仅在p53突变的MDA-MB-231细胞中具有细胞毒性，这与TNF-α的自分泌产生有关。我们提出，由于MDA-MB-231细胞中突变体p53的下调降低了TNF-αmRNA，因此p53中的功能获得性突变增强了TNF-α的转录。 p53突变细胞中cIAP的下调导致核IKK-α减少，这可能导致IKK-α介导的存活信号减少。相反，在p53野生型细胞中cIAP的下调不会导致核IKK-α的改变，共抑制因子SMRT的降解和细胞存活。我们表明，cIAP2下调的影响是上下文相关的。 p53野生型细胞中cIAP2的下调导致p53的减少以及存活和增殖信号的增加。这些结果表明，cIAP的肿瘤抑制功能可能是与cIAP突变相关的癌症（例如多发性骨髓瘤）的原因。此外，我们的数据还定义了功能获得性p53突变可能是导致IAP拮抗剂敏感性的原因。

著录项

  • 作者

    Lau, Rosanna.;

  • 作者单位

    University of Ottawa (Canada).;

  • 授予单位 University of Ottawa (Canada).;
  • 学科 Biology Cell.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 165 p.
  • 总页数 165
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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