Majid S M, Liss A S, You M, Bose H R
Section of Molecular Genetics and Microbiology, Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712-1095, USA.
Oncogene. 2006 Feb 2;25(5):756-68. doi: 10.1038/sj.onc.1209107.
The v-rel oncogene is the most efficient transforming member of the Rel/NF-kappaB family of transcription factors. v-Rel induces avian and mammalian lymphoid cell tumors and transforms chicken embryo fibroblasts in culture by the aberrant regulation of genes under the control of Rel/NF-kappaB proteins. Here we report that the expression of SH3BGRL, a member of the SH3BGR (SH3 domain-binding glutamic acid-rich) family of proteins, is downregulated in v-Rel-expressing fibroblasts, lymphoid cells, and splenic tumor cells. Chromatin immunoprecipitation experiments demonstrated that v-Rel binds to the sh3bgrl promoter in transformed cells. Coexpression of SH3BGRL with v-Rel in primary splenic lymphocytes reduced the number of colonies formed by 76%. Mutations in the predicted SH3-binding domain of SH3BGRL abolished the suppressive effect on v-Rel transformation and resulted in colony numbers comparable to those formed by v-Rel alone. However, mutations in the predicted EVH1-binding domain of SH3BGRL only had a modest effect on suppression of v-Rel transformation. This study provides the first example of a gene that is downregulated in v-Rel-expressing cells that also plays a role in v-Rel transformation.
v-rel癌基因是Rel/NF-κB转录因子家族中最有效的转化成员。v-Rel可诱导禽类和哺乳动物淋巴细胞肿瘤，并通过异常调控Rel/NF-κB蛋白控制下的基因，在培养中转化鸡胚成纤维细胞。在此我们报告，SH3BGRL（一种SH3BGR（富含SH3结构域结合谷氨酸）蛋白家族成员）在表达v-Rel的成纤维细胞、淋巴细胞和脾肿瘤细胞中表达下调。染色质免疫沉淀实验表明，v-Rel在转化细胞中与sh3bgrl启动子结合。在原代脾淋巴细胞中，SH3BGRL与v-Rel共表达使形成的集落数量减少了76%。SH3BGRL预测的SH3结合结构域中的突变消除了对v-Rel转化的抑制作用，并导致集落数量与单独由v-Rel形成的集落数量相当。然而，SH3BGRL预测的EVH-1结合结构域中的突变对v-Rel转化的抑制作用仅产生适度影响。本研究提供了第一个在表达v-Rel的细胞中表达下调且在v-Rel转化中起作用的基因实例。
