Role and Activation Status of IRS1/2 in IL-4-induced Protection from Cell Death.

IRS1/2 在 IL-4 诱导的细胞死亡保护中的作用和激活状态。

• 批准号: 8006677
• 负责人: Holly Alicia Porter
• 金额: $ 3.24万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006677
• 关键词: Apoptosis; Apoptotic; Basophils; Breast Cancer Cell; Cell Cycle; Cell Death; Cell Proliferation; Cells; Cyclins; Data; IRS1 gene; IRS2 gene; Immune response; Interleukin-4; Malignant Neoplasms; Mediating; Modeling; Molecular; Pathway interactions; Patients; Phosphorylation; Proteins; Publishing; Regulation; Resistance; Role; STAT protein; STAT6 gene; Signal Pathway; System; T-Lymphocyte; Testing; base; c-myc Genes; cell type; chemotherapy; cytokine; design; eosinophil; in vivo; mast cell; neoplastic cell; prevent; programs; public health relevance; response; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): IL-4 is a cytokine with many functions that is produced mainly by TH2 cells, basophils, and mast cells, but is also expressed by NK T cells, gamma/delta T cells, and eosinophils. There are two main signaling pathways activated by IL-4; the STAT6, signal transducers and activators of transcription, pathway that results in expression of IL-4-responsive genes and the IRS1/2 signaling pathway that influences cellular proliferation and survival. Having a decreased Th1/Th2 ratio is observed in many cancers and although this impairs cytotoxity against tumors, cytokines such as IL-4 do not act simply by modulating the immune response. IL-4 can also act directly on many tumor cell types to prevent apoptosis. Both the STAT6 pathway and the IRS1/IRS2 proteins have been associated with cancer due to their impact on regulation of anti-apoptotic proteins and control of cell proliferation. Most studies have focused solely on the contribution of the STAT6 pathway and its ability to upregulate Bcl-xL. Fewer studies have examined the role and activation status of IRS1 or IRS2 in IL-4-induced protection from cell-death. Based on the published findings and our preliminary data, we propose that IRS1 and IRS2 differentially contribute to the responsiveness of cells to chemotherapy. We have found that expression of IRS1 leads to enhanced sensitivity to chemotherapy-induced cell death in 32D cells. We hypothesize that these effects are mediated through the differential phosphorylation of IRS1 and IRS2, and the activation or inactivation of downstream regulators of the cell cycle (i.e. c-myc, p27, cyclins, and CDKs) and apoptosis (i.e. Bcl- xL, cFlipL, pAkt). Two specific aims are designed to test this hypothesis. Aim 1 is to define the role of IRS1 and IRS2 in sensitivity to chemotherapy in the model 32D cell system. Aim 2 is to analyze the role of IRS1 and IRS2 in breast cancer cell resistance to chemotherapy-induced cell death. The ability to antagonize enhanced STAT6 and/or IRS1/2 activation may provide therapeutic targets to efficiently inhibit cancer progression. Understanding the molecular programming of a cell may also allow for the better prediction of a patient's response to treatment.

描述（由申请人提供）：IL-4是一种具有多种功能的细胞因子，主要由TH2细胞、嗜碱性细胞和肥大细胞产生，但也由NK T细胞、γ / δ T细胞和嗜酸性细胞表达。IL-4激活了两种主要的信号通路；STAT6，转录的信号转导和激活因子，导致il -4应答基因表达的途径，以及影响细胞增殖和存活的IRS1/2信号通路。在许多癌症中观察到Th1/Th2比率降低，尽管这损害了对肿瘤的细胞毒性，但细胞因子如IL-4并不仅仅通过调节免疫反应起作用。IL-4还能直接作用于多种肿瘤细胞，防止细胞凋亡。STAT6通路和IRS1/IRS2蛋白都与癌症有关，因为它们对抗凋亡蛋白的调控和细胞增殖的控制有影响。大多数研究只关注STAT6通路的作用及其上调Bcl-xL的能力。很少有研究检测IRS1或IRS2在il -4诱导的细胞死亡保护中的作用和激活状态。基于已发表的研究结果和我们的初步数据，我们提出IRS1和IRS2对细胞对化疗的反应性有不同的贡献。我们发现，IRS1的表达导致32D细胞对化疗诱导的细胞死亡的敏感性增强。我们假设这些作用是通过IRS1和IRS2的差异磷酸化，以及细胞周期下游调节因子（如c-myc、p27、cyclins和CDKs）和细胞凋亡（如Bcl- xL、cFlipL、pAkt）的激活或失活介导的。为了验证这一假设，设计了两个具体目标。目的1是明确IRS1和IRS2在32D模型细胞系统中对化疗敏感性的作用。目的2分析IRS1和IRS2在乳腺癌细胞抵抗化疗诱导的细胞死亡中的作用。抗STAT6和/或IRS1/2激活增强的能力可能为有效抑制癌症进展提供治疗靶点。了解细胞的分子程序也可以更好地预测病人对治疗的反应。