Signal Transduction of Type 1 Interferons in Malignant Cells

1 型干扰素在恶性肿瘤细胞中的信号转导

• 批准号: 8583120
• 负责人: LEONIDAS C. PLATANIAS
• 金额: $ 29.89万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583120
• 关键词: AKT1 gene; Accounting; Address; Affect; Antineoplastic Agents; Antitumor Response; Biological; Characteristics; Clinical; Cohort Effect; Complete Hydatidiform Moles; Complex; Data; Development; Disease remission; Elements; Eukaryotic Initiation Factor-4E; Event; Exhibits; Funding; Gene Expression; Generations; Genes; Genetic Transcription; Genetic Translation; Growth; Growth Factor Receptors; Hematopoietic; Immunologic Surveillance; In Vitro; Indium; Interferon Activation; Interferon Receptor; Interferons; Lead; Leukemic Cell; Malignant Neoplasms; Molecular; Mus; Myeloproliferative disease; Natural Immunity; Oncogenic; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Process; Property; Protein Isoforms; Proto-Oncogene Proteins c-akt; Resistance; Role; Serine; Signal Transduction; Specificity; Structure; System; Transcriptional Activation; Tumor Suppressor Proteins; Work; base; cancer cell; cytokine; design; human FRAP1 protein; in vivo; mouse model; neoplastic; novel; novel strategies; public health relevance; receptor; research study; response; screening; type I interferon receptor

DESCRIPTION (provided by applicant): This is a competing renewal application whose overall objective is to define the mechanisms of interferon (IFN)-signaling in malignant cells. IFNs exhibit important antineoplastic properties in vitro and in vivo and are key elements in the immune surveillance against cancer, but the mechanisms by which they generate such effects remain to be defined. We have provided the first evidence that the mTOR signaling cascade is engaged by IFN receptors (IFNRs) and regulates cap-dependent mRNA translation via control of the eukaryotic initiation factor 4E (eIF4E) and the eIF4F complex. Remarkably, our studies have provided evidence for signaling specificity and differential use of mTORC2 complexes by IFNs, as compared to oncogenic signals. Our studies suggest dual regulatory roles for mTORC2 complexes in IFN-signaling, controlling downstream pathways that regulate both transcription and mRNA translation of ISGs. The current proposal is a systematic approach to dissect the functions and roles of these complexes in IFN-signaling and to define their relevance in the generation of the antineoplastic effects of IFNs. Specific aim 1 will identify upstream IFNR-generated signals that lead to mTORC2 activation and will determine the mechanisms of specificity of mTORC2 engagement by the Type I IFNR. It includes studies to dissect the role of IFNR-associated kinases in the process; studies to define whether differential engagement of distinct Sin1 isoforms accounts for specificity in the IFN-system; and screening efforts to identif novel Rictor- and Sin1-interacting IFN-signaling elements. Specif ic aim 2 will define the mechanisms by which mTORC2 complexes control ISG expression and their roles in the generation of IFN-inhibitory responses in malignant cells. It includes experiments to define the roles of mTORC2 complexes in IFNR-activated signaling cascades that regulate transcriptional activation and mRNA translation of ISGs; experiments on the effects of IFN¿-activated mTORC2 complexes on AGC kinases; and studies to dissect the requirement of distinct downstream effector elements of mTOR pathways in the generation of IFN-antiproliferative responses. Specif ic aim 3 will examine the roles of mTOR-dependent signals in the antineoplastic effects of IFNs in Ph (-) myeloproliferative neoplasms (MPNs). JAK2V617F mouse models will be established in AKT -/-, S6K -/- and Pdcd4 -/- KO mice, and the ability of IFN¿ to induce antileukemic responses in vivo, in the presence or absence of distinct effectors of the pathway, will be assessed. The activation of IFN-dependent mTOR pathways in primary hematopoietic precursors from patients with MPNs in vitro and in vivo will be assessed and correlated with IFN-sensitivity. Altogether, these studies will advance our understanding of the signaling mechanisms controlling generation of IFN-antitumor responses and will provide important information on the events that lead to malignant cell resistance to IFNs. Ultimately, they may form the basis for new approaches to overcome IFN-resistance.

描述（由申请人提供）：这是一项竞争性更新申请，其总体目标是确定恶性细胞中干扰素（IFN）信号传导的机制。IFN在体外和体内表现出重要的抗肿瘤特性，并且是针对癌症的免疫监视的关键要素，但它们产生这种作用的机制仍有待确定。我们已经提供了第一个证据表明，mTOR信号级联是由IFN受体（IFNRs）参与，并通过控制真核起始因子4 E（eIF 4 E）和eIF 4F复合物来调节帽依赖性mRNA翻译。值得注意的是，我们的研究提供了证据的信号特异性和差异使用mTORC 2复合物的干扰素相比，致癌信号。我们的研究表明mTORC 2复合物在IFN信号传导中的双重调节作用，控制调节ISGs转录和mRNA翻译的下游途径。目前的建议是一个系统的方法来剖析这些复合物的功能和作用的IFN信号，并确定其相关性的干扰素产生的干扰素效应。特异性目标1将鉴定导致mTORC 2活化的上游IFNR产生的信号，并将确定I型IFNR与mTORC 2结合的特异性机制。 它包括研究剖析IFNR相关激酶在这一过程中的作用;研究确定不同的Sin 1亚型的差异参与是否解释了IFN系统的特异性;以及筛选鉴定新的Rictor和Sin 1相互作用的IFN信号传导元件的努力。特异性目的2将定义mTORC 2复合物控制ISG表达的机制及其在恶性细胞中产生IFN抑制应答中的作用。它包括确定mTORC 2复合物在IFNR激活的信号级联中的作用的实验，所述信号级联调节ISG的转录激活和mRNA翻译;关于IFNR激活的mTORC 2复合物对AGC激酶的影响的实验;以及剖析在产生IFN抗增殖应答中mTOR途径的不同下游效应元件的需求的研究。 具体目标3将检查mTOR依赖性信号在IFN对Ph（-）骨髓增生性肿瘤（MPN）的抑制作用中的作用。将在AKT -/-、S6 K-/-和Pdcd 4-/- KO小鼠中建立JAK 2 V617 F小鼠模型，并将评估在存在或不存在所述途径的不同效应物的情况下，IFN？在体内诱导抗白血病应答的能力。 将评估体外和体内来自患有MPN的患者的初级造血前体中IFN依赖性mTOR途径的激活并与IFN敏感性相关。总之，这些研究将推进我们的理解的信号转导机制控制IFN-抗肿瘤反应的产生，并将提供重要的信息，导致恶性肿瘤细胞对IFN的耐药性的事件。最终，它们可能成为克服IFN抗性的新方法的基础。