STAT in TNF alpha induced Apoptosis

STAT 在 TNF α 诱导的细胞凋亡中的作用

• 批准号: 6514111
• 负责人: Y. Eugene Chin
• 金额: $ 24.35万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514111
• 关键词: JAK kinase; apoptosis; binding sites; cell growth regulation; cell line; cytokine receptors; gene induction /repression; gene mutation; nuclear factor kappa beta; phosphoproteins; proline; protein protein interaction; serine; transcription factor; tumor necrosis factor alpha; tyrosine

Tumor necrosis factor-a (TNFa), a pleiotropic cytokine derived from activated macrophages and other cells, plays pivotal roles in some inflammatory, cardiovascular, and systemic diseases. TNFa is a potential anticancer agent. However, TNFa has dual but opposing effects on cell growth/survival: it inhibits growth and induces apoptosis in some cancer cells but stimulates growth and maintains survival in others. By binding to its cell surface receptors (TNFR1/TNFR2), TNJFa elicits several signaling events including activation of the Caspase cascade and NF-KB. Caspase activation or over-expression of a component(s) of this pathway often leads to apoptosis. In contrast, NF-KB activation is critical for promoting cell survival and suppressing apoptosis. Thus, TNFa's output on cell is decided by the balance between NF-KB and Caspase activation. To trigger apoptosis, TNFa needs not only to activate Caspases but also to minimize or even shut down NF-KB activation. Little is known about how TNFa suppresses NF-xB activation while triggering Caspase activation. The role of protein tyrosine phosphorylation in signal transduction has been confirmed for many cytokines but remains unclear for TNFa. The JAK (Janus kinase)-STAT (signal transducer and activator of transcription) pathway is a tyrosine phosphorylation-signaling route used by interferon and other cytokines. Several lines of evidence suggest that JAK/STAT may play an important role in TNFa's signaling events. First, TNF receptors recruit JAK/Stati especially in TNFa-sensitive cells. Second, both Jaki- and Stati-deficient cells become TNFa resistant. Third, TNFR1 signaling adapter TRADD transfection-induced apoptosis is sensitized by co-transfection with Stati. These findings lead to the following working hypothesis: phosphoStati is a signal adapter associated with TNFR1/TRADD complex. It favors TNFa-induced cell death by stabilizing the death signaling complex formation and inhibiting NF-kB activation and its subsequent gene regulation. In the proposed study, the specific aims are designed to exploit this new information as follows: (1) TNFR-mediated JAK/Stat 1 activation and the role of Stati as a signal adapter in death signal transduction will be examined. (2) The interaction between Stati and TRADD in stabilizing death-signaling complex (TNFR1-TRADD-FADD) formation will be analyzed. (3) The inhibitory role of Stati on NF-KB-mediated gene regulation will be further explored. These complimentary approaches will elucidate the fundamental role of Stati in apoptosis induction by TNa and might eventually provide a boost to cancer therapies.

肿瘤坏死因子-a (TNFa)，一种多效性细胞因子 来自活化的巨噬细胞和其他细胞，在某些方面发挥着关键作用 炎症、心血管和全身性疾病。 TNFa 是一种潜在的 抗癌剂。然而，TNFa 对细胞具有双重但相反的作用 生长/存活：它抑制某些癌细胞的生长并诱导细胞凋亡 但会刺激其他人的成长并维持生存。通过与其细胞结合 表面受体 (TNFR1/TNFR2)，TNJFa 引发多种信号转导事件 包括 Caspase 级联和 NF-KB 的激活。 Caspase 激活或 该途径的某个成分的过度表达通常会导致细胞凋亡。在 相反，NF-KB 激活对于促进细胞存活和 抑制细胞凋亡。因此，TNFa在细胞上的输出量由平衡决定 NF-KB 和 Caspase 激活之间的关系。为了触发细胞凋亡，TNFa 不仅需要 激活 Caspases 的同时也最大限度地减少甚至关闭 NF-KB 的激活。 关于 TNFa 在触发时如何抑制 NF-xB 激活目前知之甚少 胱天蛋白酶激活。蛋白质酪氨酸磷酸化在信号中的作用 许多细胞因子的转导已得到证实，但仍不清楚 肿瘤坏死因子a。 JAK（Janus 激酶）-STAT（信号转导器和激活剂） 转录）途径是酪氨酸磷酸化信号传导途径 干扰素和其他细胞因子。多项证据表明 JAK/STAT 可能在 TNFa 的信号转导事件中发挥重要作用。一、TNF受体 尤其是在 TNFa 敏感细胞中招募 JAK/Stati。其次，Jaki- 和 Stati 缺陷细胞会产生 TNFa 抗性。三、TNFR1信号适配器 共转染 TRADD 转染诱导的细胞凋亡 斯塔蒂。这些发现得出以下工作假设： phosphatStati 是 与 TNFR1/TRADD 复合物相关的信号适配器。它有利于 TNFa 诱导的 通过稳定死亡信号复合物的形成并抑制细胞死亡 NF-kB 激活及其随后的基因调控。在拟议的研究中， 旨在利用这一新信息的具体目标如下：(1) TNFR 介导的 JAK/Stat 1 激活以及 Stati 作为信号适配器的作用 将检查死亡信号转导。 (2) 之间的相互作用 Stati 和 TRADD 在稳定死亡信号复合物 (TNFR1-TRADD-FADD) 中的作用 将分析形成。 (3)Stati对NF-KB介导的抑制作用 基因调控将得到进一步探索。这些免费的方法将 阐明 Stati 在 TNa 诱导细胞凋亡中的基本作用，并可能 最终促进癌症治疗。