TUMOR NECROSIS FACTOR RECEPTOR: STRUCTURE AND FUNCTION

肿瘤坏死因子是一种单核细胞因子，由 巨噬细胞对侵入性刺激的反应。肿瘤坏死 因子可导致出血性坏死和部分消退 实验动物的肿瘤，对肿瘤细胞有细胞毒作用 文化。肿瘤坏死因子也可能是造成浪费(恶病质)的原因。 常见于慢性疾病状态，包括癌症。 我的目标是了解肿瘤坏死因子是如何产生其 单元格中的操作。肿瘤坏死因子作用的启动步骤是绑定到 膜受体。亲和标记已确定肿瘤坏死因子结合 在大鼠肝脏中的结构不同于 在其他细胞上鉴定。将特定的细胞联系起来是至关重要的 肿瘤坏死因子与其不同结合部位相互作用的反应 各种目标细胞。肿瘤坏死因子分子基础的阐明 行动还需要分离和提纯肿瘤坏死因子。 受体。 我们希望了解肿瘤坏死因子结合是如何调节的，以及 转化为细胞反应。捆绑诱导合作 肿瘤坏死因子受体之间的相互作用。此外，受体也是 不断地从(下调)中删除并添加到(上调- 调节)靶细胞的质膜。合作社 结合位点间的相互作用及细胞因子的下调和上调 肿瘤坏死因子受体的特征及其与血管内皮细胞的变化 细胞对肿瘤坏死因子的反应性。细胞因子-受体偶联 复合体对膜细胞骨架的影响及其在细胞内的变化 特定靶蛋白的磷酸化状态有两种 结合被转化为生物的机制 行为。这些事件在肿瘤坏死因子行动中的作用将是 特色化的。

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.