Mechanism of oncogenesis by Rel/NF-kappaB

Rel/NF-KB蛋白是转录因子，在调节细胞增殖、凋亡和 免疫反应。Rel/NF-KB蛋白的异常表达与人类的病理改变有关 起源于各种组织的癌症，v-Rel，这个家族中急剧转化的成员，导致快速的 淋巴细胞在体外和实验动物体内的转化。V-REL系统提供了一个很好的模型 为了确定Rel/NF-_B蛋白的致癌机制，v-Rel通过解除对细胞的调控来转化细胞 通常由Rel/NF-RD3家族成员控制的基因的表达。金黄色葡萄球菌的鉴定与表征 因此，由v-rel差异调控的靶基因将为深入了解 Rel/NF-x.B蛋白在肿瘤发生中发挥作用。 这个实验室最近的研究已经确定了一些基因是由v-rel和v-rel转录激活的 其表达有助于转化过程，ch-IAP1是凋亡抑制因子家族的成员， 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表达上调。 任何一种蛋白的表达都能增强v-Rel转化淋巴细胞的能力。相比之下，表达 反义方向的CH-IAP1或IRF-4降低了v-Rel的转化能力。除了这些蛋白质， BCL-2组分和IRF家族的其他成员受致癌基因Rel蛋白的差异调控。这些 蛋白质在调节淋巴细胞的增殖和凋亡方面发挥着重要的作用。高效的 V-Rel对细胞的转化似乎是由于它能够保护细胞免受凋亡并干扰 对增长的调控。 这项研究的目的是确定v-rel靶基因促进细胞转化的机制。这个 Ch-IAP1在Rel介导的转化中的作用将通过逆转录病毒介导的基因表达和 反义技术。Ch-IAP1转化和抑制细胞凋亡所需的功能域 将绘制功能图，将产生ch-IAP I基因敲除B细胞系，以定义该蛋白质对 V-rel对细胞凋亡的抑制作用。其他研究将确定v-Rel对基因的差异激活 B细胞嗜性变异体(S2A3v-rel)可以解释这些癌基因的靶细胞特异性。的贡献 BCL-2和IRF家族成员通过v-Rel和S2A3v-Rel向细胞的转化将被定义。最后，实验 将研究IRF-4激活细胞增殖和延长转化细胞寿命的机制 通过V-Rel。这些关于v-Rel致癌机制的研究将为深入了解 Rel/NF-KB蛋白在肿瘤发生中的作用

Rel/NF-KB 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-KB 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-_:B proteins, v-Rel transforms cells by deregulating the expression of genes normally controlled by Rel/NF-rd3 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-x.B 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-IAP I 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-KB proteins in tumorigenesis.