Heckman Caroline A, Wheeler Melissa A, Boxer Linda M
Center for Molecular Biology in Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Oncogene. 2003 Sep 11;22(39):7891-9. doi: 10.1038/sj.onc.1206639.
In follicular lymphomas with the t(14;18) translocation, there is increased expression of the bcl-2 gene, which is dependent upon regulatory elements within the bcl-2 5' flanking region and the immunoglobulin heavy-chain gene enhancers. We found that t(14;18) lymphomas expressed C/EBPalpha, which is not normally expressed in B lymphocytes. Expression of C/EBPalpha increased bcl-2 expression, and two regions of the bcl-2 P2 promoter that mediated this effect were identified. C/EBPbeta was also able to increase bcl-2 promoter activity through these sites. The 5' site was GC-rich and did not contain a C/EBP consensus sequence; however, C/EBP was observed to interact with this site both in vitro by EMSA and in vivo by chromatin immunoprecipitation assay. The 3' region contained the Cdx site, which mediates the effect of A-Myb on the bcl-2 promoter. In vivo binding studies revealed that C/EBP interacted with this region of the bcl-2 promoter as well. Decreased expression of C/EBP factors due to targeting of their transcripts by siRNA molecules resulted in downregulation of Bcl-2 protein. We conclude that C/EBPalpha and C/EBPbeta contribute to the deregulated expression of Bcl-2 in t(14;18) lymphoma cells.
在伴有t(14;18)易位的滤泡性淋巴瘤中，bcl-2基因表达增加，这依赖于bcl-2 5'侧翼区域内的调控元件和免疫球蛋白重链基因增强子。我们发现t(14;18)淋巴瘤表达C/EBPα，而其在B淋巴细胞中通常不表达。C/EBPα的表达增加了bcl-2的表达，并鉴定出介导此效应的bcl-2 P2启动子的两个区域。C/EBPβ也能够通过这些位点增加bcl-2启动子活性。5'位点富含GC，不包含C/EBP共有序列；然而，通过电泳迁移率变动分析（EMSA）在体外以及通过染色质免疫沉淀分析在体内均观察到C/EBP与该位点相互作用。3'区域包含Cdx位点，其介导A-Myb对bcl-2启动子的作用。体内结合研究表明，C/EBP也与bcl-2启动子的该区域相互作用。由于小干扰RNA（siRNA）分子靶向C/EBP因子的转录本导致其表达降低，从而致使Bcl-2蛋白下调。我们得出结论，C/EBPα和C/EBPβ促成了t(14;18)淋巴瘤细胞中Bcl-2的表达失调。
