Mechanism of oncogenesis by Rel/NF-kappaB

Rel/NF-kappaB 的肿瘤发生机制

基本信息

批准号：
7161474
负责人：
HENRY R BOSE
金额：
$ 24.3万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-01-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7161474
关键词：
Accounting Animals Apoptosis Apoptosis Inhibitor B-Lymphocytes Biological Models Birds Cell Line Cell Proliferation Cell Proliferation Regulation Cells Development Evolution Family Family member Fibroblasts Gene Activation Gene Expression Gene Expression Regulation Gene Targeting Genes Goals Growth Human Human Cancer Pathology Immune response Immune system In Vitro Inhibition of Apoptosis Interferon Regulatory Factor 2 Interferon Regulatory Factor 4 Interferons Knock-out Laboratories Lead Longevity Lymphocyte Lymphocyte Activation Lymphoid Cell Lymphoproliferative Disorders Malignant - descriptor Malignant Neoplasms Maps Mediating Modeling Molecular NF-kappa B Numbers Oncogene Proteins Oncogenes Oncogenic Pathway interactions Personal Satisfaction Play Process Protein Inhibition Proteins Regulation Reticuloendotheliosis virus Retroviridae Role Specificity Spleen System T-Lymphocyte Techniques Tissues Variant apoptosis in lymphoid cells cell growth regulation cell transformation cell type defense response human TYRP1 protein insight member protein function research study transcription factor tumor tumorigenesis uncontrolled B and T lymphocyte proliferation v-rel Oncogenes

项目摘要

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.

Rel/NF-KB 蛋白是转录因子，在细胞增殖、凋亡和细胞凋亡的调节中发挥核心作用。免疫反应。 Rel/NF-KB 蛋白的改变或异常表达与人类病理学有关对于源自多种组织的癌症，v-Rel 作为该家族中的急性转化成员，可诱导快速体外和实验动物中淋巴细胞的转化。 v-Rel系统提供了一个优秀的模型为了确定 Rel/NF-_:B 蛋白的肿瘤发生机制，v-Rel 通过解除对通常由 Rel/NF-rd3 家族成员控制的基因表达。的鉴定和表征因此，受 v-Rel 差异调节的靶基因将提供对分子机制的深入了解 Rel/NF-x.B 蛋白在肿瘤发生中发挥作用。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-IAP1，凋亡抑制剂家族的成员， IRF-4（一种干扰素调节因子）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，表达式反义方向的 ch-IAP1 或 IRF-4 会降低 v-Rel 的转化能力。除了这些蛋白质之外， Bcl-2 成分和 IRF 家族的其他成员受到致癌 Rel 蛋白的差异调节。这些蛋白质在淋巴细胞的细胞增殖和凋亡的调节中具有确定的功能。高效的 v-Rel 对细胞的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。这 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 转化和凋亡抑制所需的功能域将绘制功能图，将生成 ch-IAP I 敲除 B 细胞系，以确定该蛋白质的需求 v-Rel 对细胞凋亡的抑制。其他研究将确定 v-Rel 是否对基因进行差异激活 B 细胞趋向性变体 (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进行细胞转化将被定义。最后，实验将检查 IRF-4 激活细胞增殖并延长转化细胞寿命的机制通过 v-Rel。这些关于 v-Rel 肿瘤发生机制的研究将深入了解 Rel/NF-KB 蛋白在肿瘤发生中的作用。