Mechanism of oncogenesis by Rel/NF-kappaB

Rel/NF-kappaB 的肿瘤发生机制

• 批准号: 7341466
• 负责人: HENRY R BOSE
• 金额: $ 5.81万
• 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/7341466
• 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

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，在调节细胞增殖，凋亡和 免疫反应。 REL/NF-KB蛋白的改变或异常表达与人类的病理有关 源自该家族的急性转化成员V-Rel的各种组织的癌症，诱导了快速 体外和实验动物中淋巴细胞的转化。 V-REL系统提供了出色的模型 为了确定REL/NF-_：B蛋白的肿瘤发生的机制，V-Rel通过放松调节来改变细胞 通常由Rel/NF-RD3家族成员控制的基因的表达。识别和表征 因此，通过V-Rel差异调节的靶基因将提供对分子机制的见解 rel/nf-x.b蛋白在肿瘤发生中起作用。 该实验室的最新研究确定了许多由V-Rel和V-Rel转录激活的基因 其表达有助于转化过程，CH-AP1是抑制剂家族的成员 IRF-4是干扰素调节因子，在成纤维细胞和通过V-REL转化的淋巴样细胞中上调。 两种蛋白质的表达都增强了V-Rel转化淋巴细胞的能力。相比之下，表达 反义方向中的CH-IAP1或IRF-4降低了V-REL的转化能力。除了这些蛋白质， Bcl-2成分和IRF家族的其他成员受致癌蛋白的差异调节。这些 蛋白质在调节淋巴样细胞的细胞增殖和凋亡的调节中建立了功能。高效 通过V-Rel对细胞转化似乎是由于其保护细胞免受凋亡的能力而导致的 调节生长。 这项研究的目标是定义V-REL靶基因有助于细胞转化的机制。这 CH-IAP1在相关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的功能域转化和凋亡抑制所需的功能域 将映射功能，CH-IAP I敲除B细胞系将生成以定义该蛋白的需求 V-Rel对凋亡的抑制作用。其他研究将定义V-Rel对基因的差异激活是否激活 B细胞热带变体（S2A3V-REL）可以解释这些癌基因的靶细胞特异性。的贡献 将定义通过V-REL和S2A3V REL的BCL-2和IRF家庭成员进行细胞转化。最后，实验 将检查IRF-4激活细胞增殖并延长细胞寿命转化的机制 由V-Rel。这些关于V-REL肿瘤发生机制的研究将洞悉 肿瘤发生中的REL/NF-KB蛋白。

项目成果

Activation of the TGF-ýý/Smad signaling pathway in oncogenic transformation by v-Rel.

v-Rel 激活致癌转化中的 TGF-α/Smad 信号通路。

• DOI: 10.1016/j.virol.2011.02.002
• 发表时间: 2011
• 期刊: Virology
• 影响因子: 3.7
• 作者: Tiwari,Richa;Bargmann,William;BoseJr,HenryR
• 通讯作者: BoseJr,HenryR

Multiple tumor suppressor microRNAs regulate telomerase and TCF7, an important transcriptional regulator of the Wnt pathway.

• DOI: 10.1371/journal.pone.0086990
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hrdličková R;Nehyba J;Bargmann W;Bose HR Jr
• 通讯作者: Bose HR Jr

Insights into the evolution of mammalian telomerase: platypus TERT shares similarities with genes of birds and other reptiles and localizes on sex chromosomes.

• DOI: 10.1186/1471-2164-13-216
• 发表时间: 2012-06-01
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Hrdličková R;Nehyba J;Lim SL;Grützner F;Bose HR Jr
• 通讯作者: Bose HR Jr

Suppression of CFTR-mediated Cl secretion of airway epithelium in vitamin C-deficient mice.

维生素 C 缺乏小鼠中 CFTR 介导的气道上皮 Cl 分泌的抑制。

• DOI: 10.3346/jkms.2011.26.3.317
• 发表时间: 2011
• 期刊: Journal of Korean medical science
• 影响因子: 4.5
• 作者: Kim,Yeryung;Kim,Hyemin;Yoo,Hae-Young;Kang,JaeSeung;Kim,SungJoon;Kim,JinKyoung;Cho,HyunSung
• 通讯作者: Cho,HyunSung