NF-KB PROTEINS AND CELL SURVIVAL

描述：(改编自调查人员的摘要)目的是 研究的目的是研究核因子-B/Rel蛋白在细胞存活中的作用。 我打算利用最近产生的缺乏核因子-kB的小鼠 保护死亡信号中的IKB rela亚单位由 TNFR家族和IN对癌基因诱导的细胞凋亡的保护作用。1)肿瘤坏死因子α 对核因子-kB缺陷细胞的毒性。没有能力的基础 Rela-/-巨噬细胞和成纤维细胞在 将对促炎症细胞因子TNFpha进行研究。监管 将对Rela-/-细胞中假定的抗凋亡基因进行研究。这个 RelA的特定结构域和其他核因子-kB亚基的作用，如p50 和c-rel对肿瘤坏死因子α细胞毒性的保护作用将在 Rela-/-、p50-/-rela-/-和c-rel-/-rela-/-细胞。肿瘤细胞系 将分析对TNFpha自然敏感的核因子-kB是否是一种 保护免受肿瘤坏死因子α细胞毒性的主要决定因素。2)角色 RelA对Fas和TNFR2细胞毒的保护作用。的敏感性 T淋巴细胞对Fas和TNFR2介导的细胞死亡 调查过了。这些研究将确定RelA是否在 这些细胞具有抗凋亡或促凋亡的能力。神经酰胺 在肿瘤坏死因子α和Fas配体刺激下产生的 调节其对细胞凋亡的影响。这将由以下人员直接测试 测定Rela-/-细胞对神经酰胺的敏感性。3)表达 在瑞拉/成纤维细胞中转化癌基因。将进行研究 确定致癌ras或src能力降低的基础 转化Rela-/-3T3细胞。特别是，将进行试验。 以确定这些癌基因是否会导致Rela/-成纤维细胞的细胞死亡。 RELA将被重新引入这些细胞中，以测试是否存在原位 这种蛋白质是转化和/或防止细胞死亡所必需的。

DESCRIPTION: (adapted from the investigator's abstract) The aim of this investigation is to study the role of NF- B/Rel proteins in cell survival. I intend to take advantage of recently generated mice deficient in NF-kB and IkB RelA subunit in protection death signals generated by members of the TNFR family and in protection from oncogene-induced apoptosis. 1) TNFalpha toxicity to NF-kB deficient cells. The basis for the inability of RelA-/-macrophages and fibroblasts to survive in the presence of the proinflammatory cytokine TNFalpha will be investigated. The regulation of putative anti-apoptotic genes in RelA-/- cells will be studies. The specific domains of RelA and the role of other NF-kB subunits such as p50 and c-Rel in protection from TNFalpha cytotoxicity will be investigated in RelA-/-, p50-/-RelA-/-, and c-Rel-/-RelA-/- cells. Tumor cell lines naturally sensitive to TNFalpha will be analyzed to determine if NF-kB is a primary determinant of protection from TNFalpha cytotoxicity. 2) Role of RelA in protection from Fas and TNFR2 cytotoxicity. The sensitivity of RelA-/-T lymphocytes to Fas and TNFR2 mediated cell death will be investigated. These studies will determine whether RelA functions in an anti-apoptotic or pro-apoptotic capacity within these cells. Ceramide generated following TNFalpha and Fas-ligand stimulation has been proposed to mediate their apoptotic affects. This will be directly tested by determining the sensitivity of RelA-/- cells to ceramide. 3) Expression of transforming oncogenes in RelA-/- fibroblasts. Studies will be carried out to determine the basis for decreased capability of oncogenic ras or src to transform RelA-/-3T3 cells. In particular, experiments will be carried out to determine if these oncogenes induce cell death in RelA-/-fibroblasts. RelA will be reintroduced in these cells to test if the in situ presence of this protein is required for transformation and/or preventing cell death.