TUMOR NECROSIS FACTOR RECEPTOR: STRUCTURE AND FUNCTION

肿瘤坏死因子（TNF）是一种单核细胞因子， 巨噬细胞对侵入性刺激的反应。 肿瘤坏死 因子可诱导出血性坏死和某些 在实验动物中对肿瘤细胞具有细胞毒性， 文化 TNF也可能导致消瘦（恶病质） 通常在包括癌症的慢性疾病状态中观察到。 我的目标是了解肿瘤坏死因子是如何产生 细胞中的行为。 TNF作用的起始步骤是结合 膜受体 亲和标记已鉴定出TNF结合 在大鼠肝脏中的结构不同于那些 在其他细胞上识别。 必须将特定的细胞 对TNF与其不同结合位点相互作用的反应 各种靶细胞。 阐明TNF的分子基础 行动还需要分离和纯化TNF 受体的 我们希望了解TNF结合是如何调节的， 转化为细胞反应。 结合诱导合作 TNF受体之间的相互作用。 此外，受体 ”（注1）又说：“从上而下，从下而上，从下而上。 调节）靶细胞的质膜。 合作 结合位点之间的相互作用以及 TNF受体将被表征并与以下变化相关： 细胞对TNF的反应。 精氨酸-受体偶联 复合物的膜细胞骨架和变化， 特异性靶蛋白的磷酸化状态有两种 通过这种机制，结合被转换成生物学 行动 这些事件在TNF作用中的作用将是 表征了

Tumor necrosis factor (TNF) is a monokine produced by macrophages in response to invasive stimulation. Tumor necrosis factor can induce hemorrhagic necrosis and regression of some tumors in experimental animals and is cytotoxic to tumor cells in culture. TNF may also be responsible for the wasting (cachexia) often observed in chronic disease states including cancer. My goal is to understand how tumor necrosis factor produces its actions in cells. The initiating step in TNF action is binding to membrane receptors. Affinity labeling has identified TNF binding sites in rat liver that are structurally different from those identified on other cells. It is essential to relate specific cellular responses to interaction of TNF with its different binding sites on various target cells. Elucidation of the molecular basis for TNF action will also require the isolation and purification of the TNF receptor. We wish to understand how TNF binding is regulated and transduced into cellular responses. Binding induces cooperative interactions among TNF receptors. Also, receptors are continuously removed from (down-regulation) and added to (up- regulation) the plasma membrane of target cells. Cooperative interactions among binding sites and down- and up-regulation of the TNF receptor will be characterized and related to changes of cellular responsiveness to TNF. Coupling of cytokine-receptor complexes to the membrane cytoskeleton and changes in the phosphorylation state of specific target proteins are two mechanisms through which binding is transduced into biologic actions. The role of these events in TNF action will be characterized.