STAT in TNF alpha induced Apoptosis

肿瘤坏死因子-α(TNFa)，一种多效性细胞因子 从激活的巨噬细胞和其他细胞中，在一些 炎症性、心血管和全身疾病。TNFa是一种潜在的 抗癌剂。然而，TNFa对细胞有双重但相反的作用 生长/存活：抑制某些癌细胞的生长并诱导其凋亡 而是刺激其他动物的生长并维持它们的生存。通过绑定到其细胞 表面受体(TNFR1/TNFR2)，TNJFa可引发多种信号事件 包括激活Caspase级联和核因子-kB。Caspase激活或 该通路的一个组成部分(S)的过度表达通常会导致细胞凋亡。在……里面 相比之下，核因子-KB的激活对于促进细胞存活和 抑制细胞凋亡。因此，细胞上的TNFa产量由余额决定 核因子-kB和半胱氨酸氨基转移酶激活之间的关系。要触发细胞凋亡，TNFa不仅需要 以激活Caspase，但也可以最小化甚至关闭NF-KB的激活。 关于TNFa如何在触发时抑制核因子-xB的激活，人们知之甚少 半胱氨酸酶的激活。蛋白质酪氨酸磷酸化在信号转导中的作用 许多细胞因子的转导已被证实，但仍不清楚 TNFa。JAK(Janus Kinase)-STAT(信号转导和激活因子) 转录)途径是酪氨酸磷酸化-信号通路，由 干扰素和其他细胞因子。有几条证据表明JAK/STAT 可能在TNFa的信号转导事件中发挥重要作用。第一，肿瘤坏死因子受体 招募JAK/STATI，特别是在对TNFa敏感的细胞中。其次，Jaki-和 STATI缺乏的细胞对TNFa产生抗性。第三，TNFR1信号转接器 与TRANDD共转染致敏TRAND基因诱导的细胞凋亡 斯塔蒂。这些发现导致了以下工作假说：phosphStati是 与TNFR1/Tradd复合体相关的信号适配器。它支持由TNFa诱导的 稳定死亡信号复合体的形成和抑制细胞死亡 核因子-kB的激活及其后续的基因调控。在拟议的研究中， 利用这一新信息的具体目标如下：(1) TNFR介导的JAK/Stat 1激活及STATI作为信号转接子的作用 在死亡过程中，我们将研究信号转导。(2)中美之间的互动 STATI和TRADD在稳定死亡信号复合体中的作用(TNFR1-TRADD-FADD) 将对队形进行分析。(3)STATI对核因子-KB介导的抑制作用 基因调控将进一步探索。这些免费的方法将 STATI在TNA和MAGE诱导细胞凋亡中的基础作用 最终为癌症治疗提供助力。

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.