Regulation of Bcl-2 expression by C/EBP in t(14;18) lymphoma cells.
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.
Heckman
Caroline A
CA
Center for Molecular Biology in Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Wheeler
Melissa A
MA
Boxer
Linda M
LM
D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology; D001482:Base Composition; D001665:Binding Sites; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics*; D009154:Mutation; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering; D020218:Response Elements; D014162:Transfection; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; D018398:Homeodomain Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering