BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription
K Brocke-Heidrich, B Ge, H Cvijic, G Pfeifer, D Löffler… - Oncogene, 2006 - nature.com
K Brocke-Heidrich, B Ge, H Cvijic, G Pfeifer, D Löffler, C Henze, TW McKeithan, F Horn
Oncogene, 2006•nature.comBCL3 is a proto-oncogene affected by chromosomal translocations in some patients with
chronic lymphocytic leukemia. It is an IκB family protein that is involved in transcriptional
regulation of a number of NF-κB target genes. In this study, interleukin (IL)-6-induced BCL3
expression and its effect on survival of multiple myeloma (MM) cells were examined. We
demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence
analysis of the BCL3 gene locus revealed four potential signal transducer and activator of …
chronic lymphocytic leukemia. It is an IκB family protein that is involved in transcriptional
regulation of a number of NF-κB target genes. In this study, interleukin (IL)-6-induced BCL3
expression and its effect on survival of multiple myeloma (MM) cells were examined. We
demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence
analysis of the BCL3 gene locus revealed four potential signal transducer and activator of …
Abstract
BCL3 is a proto-oncogene affected by chromosomal translocations in some patients with chronic lymphocytic leukemia. It is an IκB family protein that is involved in transcriptional regulation of a number of NF-κB target genes. In this study, interleukin (IL)-6-induced BCL3 expression and its effect on survival of multiple myeloma (MM) cells were examined. We demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence analysis of the BCL3 gene locus revealed four potential signal transducer and activator of transcription (Stat) binding sites within two conserved intronic enhancers regions: one located within enhancer HS3 and three within HS4. Chromatin immunoprecipitation experiments showed increased Stat3 binding to both enhancers upon IL-6 stimulation. Silencing Stat3 expression by small interfering RNA (siRNA) abrogated BCL3 expression by IL-6. Using reporter gene assays, we demonstrate that BCL3 transcription depends on HS4. Mutation of the Stat motifs within HS4 abolished IL-6-dependent BCL3 induction. Furthermore, BCL3 transcription was inhibited by its own gene product. This repressive feedback is mediated by NF-κB sites within the promoter and HS3. Finally, we show that overexpression of BCL3 increases apoptosis, whereas BCL3-specific siRNA does not affect the viability of INA-6 cells suggesting that BCL3 is not essential for the survival of these cells.
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