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首页> 美国卫生研究院文献>The Journal of Experimental Medicine >The Inhibitor of Death Receptor Signaling Flice-Inhibitory Protein Defines a New Class of Tumor Progression Factors
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The Inhibitor of Death Receptor Signaling Flice-Inhibitory Protein Defines a New Class of Tumor Progression Factors

机译：死亡受体信号转导抑制蛋白的抑制剂定义了一类新的肿瘤进展因子。

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摘要

Death receptor–mediated apoptosis can be modulated by several antiapoptotic proteins, such as the FLICE (FADD [Fas-associated death domain]-like IL-1β–converting enzyme)-inhibitory proteins (FLIPs). The FLIP family includes both cellular and viral members. The Kaposi's sarcoma–associated herpesvirus protein (KSHV)-FLIP is expressed by human herpesvirus 8 (HHV-8), which is associated with malignancies such as Kaposi's sarcoma and certain lymphomas. In this paper, we demonstrate that KSHV-FLIP protects cells from Fas-mediated apoptosis by inhibiting caspase activation and permits clonal growth in the presence of death stimuli in vitro. Furthermore, we show that KSHV-FLIP can act as a tumor progression factor by promoting tumor establishment and growth in vivo. When injected into immunocompetent recipient mouse strains, murine B lymphoma cells (A20) transduced with KSHV-FLIP rapidly develop into aggressive tumors showing a high rate of survival and growth. The tumor-progressive activity of KSHV-FLIP is mediated by prevention of death receptor–induced apoptosis triggered by conventional T cells. Consequently, inhibitors of death receptor signaling can be regarded as a new class of tumor progression factors, and HHV-8–associated tumors may represent naturally occurring examples of the tumorigenic effect of such inhibitors.
机译：死亡受体介导的凋亡可以通过几种抗凋亡蛋白来调节，例如FLICE（FADD [Fas相关死亡域]-样IL-1β转化酶）抑制蛋白（FLIP）。 FLIP系列包括细胞成员和病毒成员。卡波西氏肉瘤相关的疱疹病毒蛋白（KSHV）-FLIP由人疱疹病毒8（HHV-8）表达，其与恶性肿瘤有关，例如卡波西氏肉瘤和某些淋巴瘤。在本文中，我们证明了KSHV-FLIP通过抑制caspase活化来保护细胞免受Fas介导的细胞凋亡，并允许在体外存在死亡刺激的情况下克隆生长。此外，我们显示KSHV-FLIP可以通过促进体内肿瘤的建立和生长而充当肿瘤进展因子。当注射到具有免疫能力的受体小鼠品系中时，用KSHV-FLIP转导的鼠B淋巴瘤细胞（A20）迅速发展为具有高存活率和生长率的侵袭性肿瘤。 KSHV-FLIP的肿瘤进展活性是由常规T细胞触发的死亡受体诱导的细胞凋亡的预防介导的。因此，死亡受体信号转导的抑制剂可被视为一类新的肿瘤进展因子，而与HHV-8相关的肿瘤可能代表了这种抑制剂天然的致癌作用。

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