Mechanism of oncogenesis by Rel/NF-kappaB

Rel/NF-κ B蛋白是在细胞增殖、凋亡和凋亡的调节中起核心作用的转录因子， 免疫反应。Rel/NF-κ B蛋白的改变或异常表达与人类肿瘤的病理学有关。 v-Rel是该家族的急性转化成员，它能诱导多种组织来源的癌症的快速转化， 在体外和实验动物中的淋巴细胞转化。v-Rel系统提供了一个很好的模型 为了鉴定Rel/NF-_：B蛋白的致癌机制，v-Rel通过去调节NF-_：B蛋白来转化细胞。 通常由Rel/NF-rd 3家族成员控制的基因的表达。的鉴定和表征 因此，v-Rel差异调节的靶基因将提供对以下分子机制的深入了解： Rel/NF-x.B蛋白在肿瘤发生中起作用。 该实验室最近的研究已经确定了许多由v-Rel转录激活的基因， 其表达有助于转化过程，ch-IAP 1是细胞凋亡抑制剂家族的成员， 和干扰素调节因子IRF-4在由v-Rel转化的成纤维细胞和淋巴样细胞中上调。 任一蛋白的表达增强v-Rel转化淋巴细胞的能力。相比之下， 反义方向的ch-IAP 1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家族的其他成员受到致癌Rel蛋白的差异调节。这些 蛋白质在调节淋巴细胞中的细胞增殖和细胞凋亡中具有确定的功能。有效 v-Rel对细胞的转化似乎是由于其保护细胞免于凋亡并干扰细胞生长的能力。 生长调节。 本研究的目的是确定v-Rel靶基因促进细胞转化的机制。的 ch-IAP 1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来确定， 反义技术。ch-IAP 1转化和抑制肿瘤生长所需的功能结构域 将绘制ch-IAP I功能，将产生ch-IAP I敲除B细胞系，以确定该蛋白的需求， v-Rel.进一步的研究将确定v-Rel对基因的差异激活是否 一个B细胞嗜性变体（S2 A3 v-Rel）可以解释这些癌基因的靶细胞特异性。贡献 将定义Bcl-2和IRF家族成员对v-Rel和S2 A3 v-Rel细胞转化的影响。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， 关于V-Rel这些关于v-Rel致瘤机制的研究将为深入了解v-Rel在肿瘤发生中的作用提供帮助。 肿瘤发生中的Rel/NF-KB蛋白。

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.