STAT in TNF alpha induced Apoptosis

STAT 在 TNF α 诱导的细胞凋亡中的作用

• 批准号: 6812631
• 负责人: Y. Eugene Chin
• 金额: $ 24.26万
• 依托单位: RHODE ISLAND HOSPITAL
• 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/6812631
• 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），一种多效细胞因子， 从激活的巨噬细胞和其他细胞，在一些 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：在某些癌细胞中抑制生长并诱导凋亡 而是刺激生长并维持其他物种的生存。通过与细胞结合 表面受体（TNFR 1/TNFR 2），TNJFa激发若干信号传导事件 包括半胱天冬酶级联和NF-κ B的活化。半胱天冬酶激活或 该途径的组分的过度表达通常导致细胞凋亡。在 相反，NF-κ B活化对于促进细胞存活至关重要， 抑制细胞凋亡。因此，TNF α在细胞上的输出取决于平衡 NF-κ B和Caspase激活之间的关系。为了触发细胞凋亡，TNF α不仅需要 激活胱天蛋白酶，而且使NF-κ B激活最小化甚至关闭。 关于TNFa如何抑制NF-xB激活，同时触发 半胱天冬酶激活。蛋白质酪氨酸磷酸化在信号转导中的作用 已经证实了许多细胞因子的转导，但对于 TNF α。JAK（Janus激酶）-STAT（信号转导和激活因子） 转录）途径是酪氨酸磷酸化信号传导途径， 干扰素和其它细胞因子。几条证据表明JAK/STAT 可能在TNF α的信号传导中起重要作用。首先，TNF受体 招募JAK/Stati，特别是在TNF α敏感细胞中。第二，贾基和 Stati-deficient细胞变得具有TNF α抗性。三、TNFR 1信令适配器 TRADD转染诱导的细胞凋亡通过与 斯塔蒂这些发现导致了以下工作假设： 与TNFR 1/TRADD复合物相关的信号衔接子。它有利于TNF α诱导的 通过稳定死亡信号复合物的形成和抑制 NF-κ B活化及其随后的基因调控。在拟议的研究中， 具体目标是设计利用这些新信息如下：（1） 肿瘤坏死因子受体介导的JAK/Stat 1激活和Stati作为信号衔接子的作用 将检测死亡信号转导。(2)之间的相互作用 Stati和TRADD稳定死亡信号复合物（TNFR 1-TRADD-FADD） 将分析形成。(3)Stati对NF-KB介导的抑制作用 基因调控将进一步探索。这些补充办法将 阐明Stati在TNa诱导细胞凋亡中的基本作用， 最终会促进癌症治疗的发展。