IRE1a: a Conditional Tumor Suppressor

IRE1a：有条件的肿瘤抑制因子

• 批准号: 9176751
• 负责人: ADAM b GLICK
• 金额: $ 35.96万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176751
• 关键词: Ablation; Apoptosis; Apoptotic; Automobile Driving; Binding Proteins; Biological Assay; Biology; Boxing; Cell Culture Techniques; Cell Death; Cells; Cellular Stress Response; Characteristics; Conflict (Psychology); Cultured Cells; Data; Development; Diagnostic Neoplasm Staging; Differentiation Inhibitor; Endoplasmic Reticulum; Endoribonucleases; Enzymes; Epithelial; Epithelial Cells; Equilibrium; Gene Deletion; Gene Expression; Goals; Human; Hypoxia; In Vitro; Inositol; Integral Membrane Protein; Link; Lung; MAP Kinase Gene; Malignant - descriptor; Malignant Conversion; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular Biology; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Outcome; Output; Pathogenesis; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Process; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogenes; RNA Splicing; Regulation; Resolution; Ribonucleases; Role; Signal Pathway; Signal Transduction; Somatic Mutation; Subfamily lentivirinae; Testing; Transcript; Transducers; Tumor Suppressor Proteins; actionable mutation; anti-cancer therapeutic; base; biological adaptation to stress; cancer cell; carcinogenesis; cytotoxic; endoplasmic reticulum stress; in vitro Model; in vivo; keratinocyte; mRNA Decay; mRNA Transcript Degradation; malignant phenotype; mouse model; mutant; neoplastic cell; novel; nuclease; nutrient deprivation; overexpression; pneumocyte; premature; prevent; ras Oncogene; response; senescence; transcription factor; tumor; tumor growth; tumor progression

PROJECT SUMMARY/ABSTRACT The adaptive response of cells to increased unfolded proteins within the endoplasmic reticulum, or the unfolded protein response (UPR), is a fundamental and conserved cellular survival mechanism. Cancer development is often associated with a range of cytotoxic conditions like hypoxia, nutrient deprivation, and pH changes. These conditions trigger a set of cellular stress response pathways including the ER-stress response. Many aspects of the endoplasmic reticulum (ER)-stress response are adaptive and protect tumor cells from cell death suggesting a crucial role in tumor growth. Much less is known about the role of ER-stress response pathways in early stages of cancer and tumor progression. Activating mutations in Ras proto-oncogenes are among the most common in human cancer. Mouse and human keratinocytes and primary lung epithelial cells respond to expression of oncogenic Ras with proliferation followed by premature senescence. Escape from the senescence response is directly linked to malignant progression. IRE1α is an ER transmembrane protein that has both serine/threonine kinase and endoribonuclease domains. In response to ER-stress IRE1α splices the XBP1 transcript to generate a potent transcription factor that induces expression of genes critical for resolution of ER stress, and in some studies is important in expression of genes regulating the malignant phenotype. The IRE1α nuclease also targets other mRNAs for degradation in a process called RIDD (regulated IRE1α- dependent decay), which can function in the UPR to reduce levels of mRNA’s that encode proteins processed through the ER but also mediates cell death to unremitting ER stress. Both IRE1α and spliced Xbp1 are elevated in cancer, and specific somatic mutations within the IRE1α kinase and RNase domains have been identified in cancers but the function consequences of these are unknown. The major goal of this proposal is to understand how IRE1α expression and RNase outputs modulate cellular responses to oncogenic Ras and promote or suppress Ras-driven cancer. Based on preliminary and submitted data we hypothesize that IRE1α is a conditional tumor suppressor whose actions in cancer depend on the balance between Xbp1 splicing and RIDD. We propose that both ER stress levels and Ras signal strength regulate the balance of IRE1α outputs driving the RNase towards Xbp1 splicing and proliferation or RIDD and senescence. Further we propose a new paradigm of ER stress dependent and independent RIDD targets. Id1 mRNA is a major ER stress independent, Ras dependent RIDD target whose degradation by the IRE1α RNase is essential for oncogene induced senescence. We will use mouse models of KRas-induced NSCLC and epidermal squamous cancer to test the effect of Ire1α or Xbp1 ablation, IRE1α overexpression and specific IRE1α human cancer mutations on cancer development. Together these studies will provide new and impactful information on the role of the IRE1α pathway in epithelial cell carcinogenesis and determine if IRE1α represents a significant target for anticancer therapeutics.

项目摘要/摘要 细胞对内质网内增加的未折叠蛋白的适应性反应，即 未折叠蛋白应答(UPR)是一种基本的、保守的细胞生存机制。癌 发育通常与一系列细胞毒性条件有关，如缺氧、营养缺乏和pH 改变。这些条件触发了一系列细胞应激反应途径，包括内质网应激反应。 内质网(ER)应激反应的许多方面是适应性的，并保护肿瘤细胞免受 细胞死亡表明在肿瘤生长中起着至关重要的作用。人们对内质网应激反应的作用知之甚少 癌症早期阶段和肿瘤进展的途径。激活RAS原癌基因的突变是 在人类癌症中是最常见的。小鼠和人角质形成细胞及原代肺上皮细胞 对致癌RAS表达的反应伴随着增殖和早衰。逃离这座城市 衰老反应与恶性进展直接相关。Ire 1α是一种内质网跨膜蛋白 含有丝氨酸/苏氨酸激酶和核酸内切酶结构域。作为对内质网应激的响应，IRE1α拼接 XBP1转录产生一种有效的转录因子，诱导对解析至关重要的基因的表达 在一些研究中，内质网应激在调节恶性表型的基因表达中起重要作用。这个 IRE1α核酸酶还以其他α为靶标，在一种称为RIDD(受调节的IRE1 RNA- 依赖衰变)，它可以在UPR中发挥作用，降低编码已加工蛋白质的mRNA水平 还通过内质网介导细胞死亡，以持续的内质网应激。IRE1XBP1和拼接的α都是 在癌症中升高，IRE1α激酶和核糖核酸酶结构域中的特定体细胞突变 已在癌症中发现，但这些物质的功能后果尚不清楚。这项提议的主要目标是 了解IRE1α表达和核糖核酸酶输出如何调节细胞对致癌的反应 RAS和促进或抑制RAS驱动的癌症。根据初步和提交的数据，我们 假设IRE1α是一种条件性肿瘤抑制因子，其在癌症中的作用依赖于 XBP1剪接和RIDD之间的平衡。我们认为内质网应激水平和RAS信号强度 调节IRE1RNAs输出的平衡，推动α向剪接和增殖方向发展。 衰老。此外，我们还提出了一种内质网应激依赖和独立RIDD靶点的新范式。Id1 α是一种主要的内质网应激不依赖、RAS依赖的RIDD靶标，其被IRE1RNase降解 在癌基因诱导的衰老过程中是必不可少的。我们将使用KRAS诱导的NSCLC小鼠模型和 检测表皮鳞状细胞癌IRE1α或XBP1消融效果，IRE1α过表达及特异性 IRE1α突变对人类癌症发生的影响。总之，这些研究将提供新的和有影响力的 IRE1α通路在上皮细胞癌变中作用的信息及确定IRE1α 代表了抗癌治疗的一个重要靶点。