IRE1a: a Conditional Tumor Suppressor

IRE1a：有条件的肿瘤抑制因子

• 批准号: 10212977
• 负责人: ADAM b GLICK
• 金额: $ 14.62万
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212977
• 关键词: Ablation; Apoptosis; Apoptotic; Automobile Driving; Binding Proteins; Biological Assay; Biology; Cell Culture Techniques; Cell Death; Cells; Cellular Stress Response; Characteristics; Conflict (Psychology); Cultured Cells; Data; Development; Differentiation Inhibitor; Endoplasmic Reticulum; Endoribonucleases; Enzymes; Epithelial; Epithelial Cells; Equilibrium; Gene Deletion; Gene Expression; Goals; Human; Hypoxia; In Vitro; Inositol; Integral Membrane Protein; K-ras mouse model; Lentivirus; 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; Pharmacology; Phosphorylation; Phosphorylation Site; Phosphotransferases; Process; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogenes; RNA Splicing; Regulation; Resolution; Ribonucleases; Role; Signal Pathway; Signal Transduction; Somatic Mutation; Testing; Transcript; Transducers; Tumor Suppressor Proteins; XBP1 gene; anti-cancer therapeutic; base; biological adaptation to stress; cancer cell; carcinogenesis; cytotoxic; driver mutation; 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 细胞对内质网中增加的蛋白质增加的自适应反应，或 展开的蛋白质反应（UPR）是一种基本和配置的细胞存活机制。癌症 发育通常与多种细胞毒性疾病有关，例如缺氧，营养剥夺和pH 更改。这些条件触发一组包括ER应力反应在内的细胞应力反应途径。 内质网（ER）压力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。关于ER压力反应的作用，知之甚少 在癌症和肿瘤进展的早期阶段的途径。 RAS原始基因中的激活突变是 在人类癌症中最常见的之一。小鼠和人角质形成细胞和原发性肺上皮细胞 对致癌性RA的表达反应，然后增生，然后进行过早感应。逃脱 感应反应与恶性进展直接相关。 IRE1α是一种ER跨膜蛋白 具有丝氨酸/苏氨酸激酶和内核酸酶域。响应ER应力IRE1α拼接 XBP1转录本以产生一个潜在的转录因子，影响基因表达对分辨率至关重要 ER应激的含量，在某些研究中对于控制恶性表型的基因表达很重要。 IRE1α核酸酶还靶向其他mRNA，以降解在一个称为RIDD的过程中（受调节的IRE1α- 依赖性衰减），它可以在UPR中起作用以减少编码已处理蛋白质的mRNA水平 通过ER，但也会介导细胞死亡，以使ER压力不利于ER。 IRE1α和剪接的XBP1都是 IRE1α激酶和RNase结构域内的癌症升高以及特定的体细胞突变已是 在癌症中鉴定出来，但这些功能后果尚不清楚。该提议的主要目标是 了解IRE1α表达和RNase如何调节细胞对致癌性的反应 RAS并促进或抑制由RAS驱动的癌症。基于初步和提交的数据我们 假设IRE1α是一种有条件的肿瘤抑制因子，其在癌症中的作用取决于 在XBP1剪接和RIDD之间保持平衡。我们提出ER应力水平和RAS信号强度 调节将RNase驱动XBP1拼接和增殖或RIDD的IRE1α输出的平衡 衰老。此外，我们提出了一个新的ER应力依赖性和独立RIDD目标的范式。 ID1 mRNA是一个主要的ER胁迫独立的，依赖RAS的RIDD靶标，其IRE1αRNase降解 对于癌基因诱导的感应至关重要。我们将使用KRAS诱导的NSCLC的鼠标模型和 表皮鳞癌测试IRE1α或XBP1消融，IRE1α过表达和特定的影响 IRE1α人癌突变对癌症的发展。这些研究将共同​​提供新的和有影响力的 有关IRE1α途径在上皮细胞癌发生中的作用的信息，并确定IRE1α是否 代表了抗癌治疗的重要目标。

项目成果

TGFβ1 regulates HRas-mediated activation of IRE1α through the PERK-RPAP2 axis in keratinocytes.

• DOI: 10.1002/mc.23453
• 发表时间: 2022-10
• 期刊: Molecular carcinogenesis
• 影响因子: 4.6

The Endoplasmic Reticulum Stress Sensor IRE1α Regulates the UV DNA Repair Response through the Control of Intracellular Calcium Homeostasis.

• DOI: 10.1016/j.jid.2021.11.010
• 发表时间: 2022-06
• 期刊: JOURNAL OF INVESTIGATIVE DERMATOLOGY
• 影响因子: 6.5
• 作者: Son, Jeongin;Mogre, Saie;Chalmers, Fiona E.;Ibinson, Jack;Worrell, Stephen;Glick, Adam B.
• 通讯作者: Glick, Adam B.