TRANSFORMATION BY AVIAN RETICULOENDOTHELIOSIS VIRUS

描述：(改编自《调查者摘要》)：禽类 网状内皮组织增生症病毒(REV-T)是所有逆转录病毒中毒力最强的 很快就会导致致命的淋巴瘤。V-Rel是致癌性最强的 Rel/NF-KB转录因子家族的成员。REI/NF-KB家族 调节与增殖、凋亡、防御有关的基因的表达 以及伤口愈合反应和胚胎发育。REI/NF-KB复合体与 DNA识别基序为二聚体。V-rel的转换是以下结果 对通常由REI/NF-KB家族控制的基因的差异调控。 在转化细胞的细胞核中，v-rel以同源二聚体或 含有c-REI、NF-KBL和NF-KB2的杂二聚体。自从……出现以来 核内V-受体异源二聚体在时间上与细胞内 细胞增殖率、v-Rel与内源性REI/NF-KB的关系 家庭成员很可能在它的转型能力中发挥关键作用。 我们已经分离出了v-rel的点突变，它们已经失去了 与特定的REI/NF-KB家庭成员联系，并建议聘用这些成员 点突变以确定哪些REI/NF-KB家族成员使v-REL能够 变形。 V-rel的过度表达导致c-fos和c-fos的表达升高 C-jun和Fra-2在成纤维细胞培养和淋巴组织中的抑制表达 细胞。C-jun已经被证明是直接转录上调的 V-REI。成纤维细胞培养物或淋巴样细胞的混合感染或顺序感染 逆转录病毒表达v-rel和一个转显性负性突变体的细胞 AP-1活性，supjun-1，导致转化减少 V-REL的效率。这些研究没有定义单个AP-1的作用 家庭成员。C-jun、c-fos和fra-2在v-Rel介导中的作用 我们将对转型进行考察。我们还建议确定V-Rel是否 直接调控c-fos和fra-2的差异表达。 最近，我们发现Rho家族小分子GTP酶家族的成员TClO， 在v-Rel转化的成纤维细胞中上调。由于TCIO和其他RHO 蛋白质与肌动蛋白细胞骨架的组织有关，它 TC10介导的信号转导通路可能是 成纤维细胞中观察到的细胞骨架重塑 通过v-Rel进行变换。此外，TCIO还激活c-jun氨基末端激酶 (JNK)，它磷酸化并激活c-jun。因此，V-Rel可以调节 AP-1的活性不仅在转录水平上，而且在 翻译后水平通过TC1O激活途径。的最终目标是 这项提议是为了确定TCIO是否在v-REI介导的过程中发挥作用 转型。

DESCRIPTION: (Adapted from the Investigator's abstract):Avian reticuloendotheliosis virus (REV-T) is the most virulent of all retroviruses and rapidly induces an invariably fatal lymphoma. v-Rel is the most oncogenic member of the Rel/NF-KB family of transcription factors. The ReI/NF-KB family regulates the expression of genes involved in proliferation, apoptosis, defense and wound healing responses, and embryogenesis. The ReI/NF-KB complexes bind to DNA recognition motifs as dimers. Transformation by v-Rel is the result of differential regulation of genes normally controlled by the ReI/NF-KB family. In the nuclei of transformed cells, v-Rel exists as homodimers or in heterodimers with c-ReI, NF-KBl, and NF-KB2. Since the appearance of v-Relheterodimers in the nucleus temporally correlates with an increase in the rate of cell proliferation, the association of v-Rel with endogenous ReI/NF-KB family members is likely to play a critical role in its transforming ability. We have isolated point mutants of v-Rel which have lost their ability to associate with specific ReI/NF-KB family members and propose to employ these point mutants to determine which ReI/NF-KB family members enable v-Rel to transform. The overexpression of v-Rel, results in the elevated expression of c-fos and c-jun and in repressed expression of fra-2 in fibroblast cultures and lymphoid cells. c-jun has been shown to be directly transcriptionally upregulated by v-ReI. Co-infection or sequential infection of fibroblast cultures or lymphoid cells with retroviruses expressing v-rel and a transdominant negative mutant of AP-1 activity, supjun-1, resulted in a reduction of the transformation efficiency of v-Rel. These studies did not define the role of individual AP-1 family members. The role of c-Jun, c-fos, and fra-2 in v-Rel-mediated transformation will be examined. We also propose to determine whether v-Rel directly regulates the differential expression of c-fos and fra-2. Recently, we have found that TClO, a member of the Rho family of small GTPases, is upregulated in v-Rel transformed fibroblasts. Since TCIO and other Rho proteins have been implicated in the organization of the actin cytoskeleton, it is possible that the TC1O-mediated signal transduction pathway may be responsible for the cytoskeletal remodeling observed in fibroblast transformation by v-Rel. In addition, TCIO activates c-Jun N-terminal kinase (JNK) which phosphorylates and activates c-Jun. v-Rel may, therefore, regulate AP-1 activity not only at the transcriptional level, but also at the post-translational level through the TC1O activation pathway. The last aim of this proposal is to determine if TCIO plays a role in v-ReI-mediated transformation.