Mechanism of oncogenesis by Rel/NF-kappaB

Rel/NF-kappaB 的肿瘤发生机制

• 批准号: 7006101
• 负责人: HENRY R BOSE
• 金额: $ 25.03万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006101
• 关键词: Mechanism; oncogenesis; Rel; NF; kappaB

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.

描述（由申请人提供）：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源自多种组织的人类癌症的病理学有关，v-Rel 是该家族的急性转化成员，在体外和实验中诱导淋巴细胞的快速转化动物。 v-Rel 系统提供了一个极好的模型来识别 Rel/NF-kappaB 蛋白的肿瘤发生机制，v-Rel 通过解除通常由 Rel/NF-kappaB 家族成员控制的基因的表达来转化细胞。因此，受 v-Rel 差异调节的靶基因的鉴定和表征将有助于深入了解 Rel/NF-kappaB 蛋白在肿瘤发生中发挥作用的分子机制。该实验室最近的研究发现了许多由 v-Rel 转录激活且其表达有助于转化过程的基因、凋亡抑制剂家族成员 ch-IAP1 和干扰素 IRF-4调节因子，在 v-Rel 转化的成纤维细胞和淋巴细胞中上调。任一蛋白的表达都会增强 v-Rel 转化淋巴细胞的能力。相比之下，反义方向的 ch-IAP1 或 IRF-4 表达降低了 v-Rel 的转化能力。除了这些蛋白之外，Bcl-2 成分和 IRF 家族的其他成员也受到致癌 Rel 蛋白的差异调节。这些蛋白质在调节淋巴样细胞的细胞增殖和凋亡方面具有确定的功能。 v-Rel 对细胞的有效转化似乎是由于它能够保护细胞免于凋亡并干扰生长调节。本研究的目标是确定 v-Rel 靶基因促进细胞转化的机制。 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来确定。将绘制 ch-IAP1 中转化和凋亡抑制功能所需的功能域，并生成 ch-IAP1 敲除 B 细胞系，以确定该蛋白通过 v-Rel 抑制凋亡的需要。其他研究将确定 v-Rel 和 B 细胞趋向性变体 (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 Bcl-2 和 IRF 家族成员对 v-Rel 和 S2A3v-Rel 细胞转化的贡献。最后，实验将检查 IRF-4 激活细胞增殖并延长 v-Rel 转化细胞寿命的机制。这些关于 v-Rel 肿瘤发生机制的研究将深入了解 Rel/NF-kappaB 蛋白在肿瘤发生中的贡献。