A Critical Role for Stat2 in Type 1 Intferon-Induced Apoptosis

Stat2 在 1 型干扰素诱导的细胞凋亡中的关键作用

• 批准号: 7690895
• 负责人: ANA M GAMERO
• 金额: $ 16.05万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-23 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690895
• 关键词: Apoptosis; Role

Interferons (IFNs) have become extremely useful cytokines in the treatment of cancer and viral diseases due to their antigrowth, antiviral and immunomodulatory properties. The biological actions of IFNs are mediated by expression of early responsive genes regulated in part by the activation of the Jak/Stat signaling pathway. The antiproliferative actions of type I IFNs in Jurkat cells, a human T cell line, require activation of a set of T cell receptor (TCR) signaling components: protein tyrosine kinases and a protein tyrosine phosphatase. Stimulation of Jurkat cells with IFN-beta induces nuclear translocation of NFAT, a transcription factor activated in response to TCR stimulation. To explore the role of NFAT in type I IFN signaling, Jurkat cells were transfected with a NFAT driven luciferase reporter. Incubation of cells with IFN-beta inhibited PMA and ionomycin induced NFAT dependent transcription. This negative regulatory effect was reversed by expression of a dominant negative Stat1 mutant. Conversely, treatment of Jurkat cells with ionomycin inhibited IFN-beta induced transcriptional activity of an ISRE driven luciferase reporter that is reversible by pretreatment of cells with cyclosporine A (CsA), a specific inhibitor of calcineurin, the upstream activator of NFAT. Incubation of normal peripheral blood T cells with PMA plus ionomycin inhibited the expression of specific IFN inducible genes and CsA restored expression of these genes. Moreover, Stat1 and NFAT proteins are associated in T cells. These results provide first evidence for the involvement of NFAT in type I IFN regulated signaling cascades in T cells. We will test the hypothesis that NFAT and Stat1 reciprocally repress each others’ transcriptional activities by performing the following aims: (1) Determine whether incubation of T cells with IFN-beta in combination with T-cell receptor agonists alters NFAT or Stat1 activation, binding to DNA or nuclear localization. (2) Determine the domains of Stat1 and NFAT that are required for these proteins to interact and whether this interaction is required for these factors to regulate gene expression.

干扰素 (IFN) 因其抗生长、抗病毒和免疫调节特性而成为治疗癌症和病毒性疾病中极其有用的细胞因子。 IFN 的生物学作用是由早期反应基因的表达介导的，而早期反应基因的表达部分受 Jak/Stat 信号通路的激活调节。抗增殖剂 I 型干扰素在人类 T 细胞系 Jurkat 细胞中的作用需要 一组 T 细胞受体 (TCR) 信号传导成分的激活：蛋白质 酪氨酸激酶和蛋白酪氨酸磷酸酶。 Jurkat的刺激 具有 IFN-β 的细胞会诱导 NFAT（一种转录）的核转位 响应 TCR 刺激而激活的因子。为了探索 NFAT 在 I 型 IFN 信号传导中的作用，用 NFAT 驱动的荧光素酶报告基因转染 Jurkat 细胞。细胞与 IFN-β 一起孵育可抑制 PMA 和离子霉素诱导的 NFAT 依赖性转录。这种负调控效应可通过显性负性 Stat1 突变体的表达而逆转。相反，用离子霉素处理 Jurkat 细胞会抑制 IFN-β 诱导的 ISRE 驱动的荧光素酶报告基因的转录活性，而这种活性可通过用环孢菌素 A (CsA) 预处理细胞来逆转，环孢菌素 A (CsA) 是钙调神经磷酸酶（NFAT 上游激活剂）的特异性抑制剂。将正常外周血 T 细胞与 PMA 加离子霉素一起孵育可抑制特定 IFN 诱导基因的表达，而 CsA 可恢复这些基因的表达。此外，Stat1 和 NFAT 蛋白与 T 细胞相关。这些结果为 NFAT 参与 T 细胞中 I 型 IFN 调节的信号级联反应提供了第一个证据。我们将通过执行以下目标来检验 NFAT 和 Stat1 相互抑制彼此转录活性的假设：（1）确定 T 细胞与 IFN-β 与 T 细胞受体激动剂联合孵育是否会改变 NFAT 或 Stat1 的激活、与 DNA 的结合或核定位。 (2) 确定这些蛋白质相互作用所需的 Stat1 和 NFAT 结构域，以及这些因子调节基因表达是否需要这种相互作用。

项目成果

STAT2 contributes to promotion of colorectal and skin carcinogenesis.

• DOI: 10.1158/1940-6207.capr-09-0105
• 发表时间: 2010-04
• 期刊: Cancer prevention research (Philadelphia, Pa.)
• 作者: Gamero AM;Young MR;Mentor-Marcel R;Bobe G;Scarzello AJ;Wise J;Colburn NH
• 通讯作者: Colburn NH

Resistance to IFN-alpha-induced apoptosis is linked to a loss of STAT2.

• DOI: 10.1158/1541-7786.mcr-08-0344
• 发表时间: 2010-01
• 期刊: Molecular cancer research : MCR
• 作者: Romero-Weaver AL;Wang HW;Steen HC;Scarzello AJ;Hall VL;Sheikh F;Donnelly RP;Gamero AM
• 通讯作者: Gamero AM

Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells.

• DOI: 10.1038/ni.3308
• 发表时间: 2016-01
• 期刊: NATURE IMMUNOLOGY
• 影响因子: 30.5
• 作者: Duerr, Claudia U.;McCarthy, Connor D. A.;Mindt, Barbara C.;Rubio, Manuel;Meli, Alexandre P.;Pothlichet, Julien;Eva, Megan M.;Gauchat, Jean-Francois;Qureshi, Salman T.;Mazer, Bruce D.;Mossman, Karen L.;Malo, Danielle;Gamero, Ana M.;Vidal, Silvia M.;King, Irah L.;Sarfati, Marika;Fritz, Joerg H.
• 通讯作者: Fritz, Joerg H.