BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

University of Nebraska at Omaha, Omaha, Nebraska, United States
Oncogene (Impact Factor: 8.46). 12/2006; 25(55):7297-304. DOI: 10.1038/sj.onc.1209711
Source: PubMed


BCL3 is a proto-oncogene affected by chromosomal translocations in some patients with chronic lymphocytic leukemia. It is an IkappaB family protein that is involved in transcriptional regulation of a number of NF-kappaB 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-kappaB 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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Available from: Friedemann Horn, Oct 08, 2014
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    • "In contrast to cytoplasmic IκBs that are degraded in response to many stimulatory signals, Bcl-3 does not undergo regulatory proteolysis. However, the role of Bcl-3 in modulating NF-κB activity has been controversial [21], [22], [23], [24], [25], [26], [27], [28]. It is suggested that overexpression of Bcl-3 can cause dysregulation of genes normally regulated by NF-κB transcription factors to affect cell proliferation, differentiation and apoptosis [20]. "
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