Oct transcription factors mediate t(14;18) lymphoma cell survival by directly regulating bcl-2 expression.
Oct-1 and Oct-2 are members of the POU homeodomain family of transcriptional regulators and are critical for normal embryonic development. Gene-targeting studies showed that Oct-1 and Oct-2 are largely dispensable for B-cell development and immunoglobulin production, although both Oct-2 and Bob-1 are required for a proper immune response and germinal center formation. In these studies, we investigated the role of Oct factors in B-cell lymphomas. Recent investigations have shown increased expression of Oct-2 and Bob-1 in lymphomas, and we observed greatly increased levels of Oct-2 in lymphoma cells with the t(14;18) translocation. Decreased expression of Oct-1, Oct-2, or Bob-1 by RNA interference resulted in apoptosis and down-regulation of bcl-2 expression. Furthermore, Oct-2 induced bcl-2 promoter activity and mediated this effect through three regions in the bcl-2 P2 promoter. Although these regions did not contain canonical octamer motifs, we observed the direct interaction of Oct-2 with all three sites both in vitro by EMSA and in vivo by chromatin immunoprecipitation assay. Moreover, by mutation analysis we found that the ability of Oct-2 to activate bcl-2 required C/EBP, Cdx, and TATA-binding sites. Oct-2, therefore, acts as a cell survival factor in t(14;18) lymphoma cells by directly activating the antiapoptotic gene bcl-2.
Heckman
C A
CA
Center for Molecular Biology in Medicine, Palo Alto VAHCS, Palo Alto, CA, USA.
Duan
H
H
Garcia
P B
PB
Boxer
L M
LM
D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism; D050813:Octamer Transcription Factor-2 / Q000235:genetics / Q000378:metabolism; D050810:Octamer Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D022762:CCAAT-Enhancer-Binding Proteins; C491273:CDX1 protein, human; D018398:Homeodomain Proteins; D050811:Octamer Transcription Factor-1; D050813:Octamer Transcription Factor-2; D050810:Octamer Transcription Factors; C091546:POU2AF1 protein, human; C058435:POU2F2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators