Mechanism of oncogenesis by Rel/NF-kappaB

描述(申请人提供)：Rel/NF-kappaB蛋白是转录因子，在细胞增殖、凋亡和免疫反应的调节中发挥核心作用。Rel/NF-kappaB蛋白的改变或异常表达与多种组织来源的人类肿瘤的病理过程有关，v-Rel是该家族中的一个急性转化成员，在体外和实验动物中诱导淋巴细胞的快速转化。V-Rel系统为研究Rel/NF-kappaB蛋白的致癌机制提供了一个很好的模型，v-Rel通过解除对通常由Rel/NF-kappaB家族成员调控的基因表达的调控而转化细胞。因此，对v-Rel差异调控靶基因的识别和鉴定将有助于深入了解Rel/NF-kappaB蛋白在肿瘤发生中的分子机制。本实验室最近的研究已经确定了一些由v-Rel转录激活并参与转化过程的基因，其中凋亡抑制家族成员ch-IAP1和干扰素调节因子IRF-4在v-Rel转化的成纤维细胞和淋巴样细胞中上调。任何一种蛋白的表达都能增强v-Rel转化淋巴细胞的能力。相反，在反义方向表达ch-IAP1或IRF-4会降低v-Rel的转化能力。除了这些蛋白外，Bcl2组分和IRF家族的其他成员都受到致癌基因Rel蛋白的不同调控。这些蛋白在调节淋巴细胞的增殖和凋亡方面发挥了重要作用。V-Rel对细胞的高效转化似乎源于其保护细胞免受凋亡和干扰生长调节的能力。这项研究的目的是确定v-rel靶基因促进细胞转化的机制。通过逆转录病毒介导的基因表达和反义技术，将确定ch-IAP1在REL介导的转化中的作用。将绘制ch-IAP1的转化和抑制凋亡功能所需的功能结构域，并建立ch-IAP1基因敲除的B细胞系，以确定该蛋白对v-Rel抑制凋亡的需求。进一步的研究将确定v-Rel和B细胞嗜性变异体(S2A3v-Rel)对基因的差异激活是否可以解释这些癌基因的靶细胞特异性。将定义Bcl2和IRF家族成员在v-Rel和S2A3v-Rel的细胞转化中的作用。最后，实验将检验IRF-4激活细胞增殖和延长v-Rel转化细胞寿命的机制。这些对v-Rel致癌机制的研究将有助于深入了解Rel/NF-kappaB蛋白在肿瘤发生中的作用。

DESCRIPTION (provided by applicant): Rel/NF-kappaB proteins are transcription factors that play a central role in the regulation of cell proliferation, apoptosis, and immune responses. The altered or aberrant expression of Rel/NF-kappaB proteins is implicated in the pathology of human cancers derived from a variety of tissues, v-Rel, the acutely transforming member of this family, induces the rapid transformation of lymphocytes in vitro and in experimental animals. The v-Rel system has provided an excellent model to identify the mechanisms of oncogenesis by Rel/NF-kappaB proteins, v-Rel transforms cells by deregulating the expression of genes normally controlled by Rel/NF-kappaB family members. The identification and characterization of target genes differentially regulated by v-Rel will, therefore, provide insight into the molecular mechanisms by which Rel/NF-kappaB proteins function in tumorigenesis. Recent studies in this laboratory have identified a number of genes that are transcriptionally activated by v-Rel and whose expression contributes to the transformation process, ch-IAP1, a member of the inhibitor-of-apoptosis family, and IRF-4, an interferon regulatory factor, are upregulated in fibroblasts and lymphoid cells transformed by v-Rel. Expression of either protein enhances the ability of v-Rel to transform lymphocytes. By contrast, expression of ch-IAP1 or IRF-4 in the antisense orientation reduces the transforming ability of v-Rel. In addition to these proteins, Bcl-2 components and other members of the IRF family are differentially regulated by oncogenic Rel proteins. These proteins have established functions in the regulation of cell proliferation and apoptosis in lymphoid cells. The efficient transformation of cells by v-Rel appears to result from its ability to protect cells from apoptosis and interfere with the regulation of growth. The goals of this study are to define the mechanisms by which v-Rel target genes contribute to cell transformation. The role of ch-IAP1 in Rel-mediated transformation will be established by retrovirus-mediated gene expression and antisense techniques. The functional domains in ch-IAP1 required for its transforming and apoptosis-suppressing functions will be mapped, ch-IAP1 knockout B cell lines will be generated to define the requirement of this protein for the inhibition of apoptosis by v-Rel. Additional studies will define whether the differential activation of genes by v-Rel and a B cell tropic variant (S2A3v-Rel) can account for the target cell specificity of these oncogenes. Contributions of Bcl-2 and IRF family members to cell transformation by v-Rel and S2A3v-Rel will be defined. Finally, experiments will examine the mechanisms by which IRF-4 activates cell proliferation and extends the life span of cells transformed by v-Rel. These studies on the mechanisms of oncogenesis by v-Rel will provide insight into the contributions of Rel/NF-kappaB proteins in tumorigenesis.