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

Institute of Clinical Immunology and Transfusion Medicine, University of Leipzig, Leipzig, Germany.
Oncogene (Impact Factor: 8.46). 12/2006; 25(55):7297-304. DOI: 10.1038/sj.onc.1209711
Source: PubMed

ABSTRACT 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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    ABSTRACT: Epigenetic factor CTCF (CCCTC binding factor) plays important roles in genetic controls of the cell fate. Previous studies found in corneal epithelial cells that CTCF is regulated by epidermal growth factor (EGF) through activation of NF-κB p65/p50. It also found that CTCF is suppressed in ultraviolet (UV) stress-induced corneal epithelial cells. However, it is still unknown how UV stress down-regulates CTCF affecting the cell fate. In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription. Unlike the effect of EGF, UV stress-induced Bcl-3 activation suppressed CTCF activity without involving the IκBα and p65 pathway. Thus, results of the study reveal a novel mechanism for regulatory control of CTCF in UV stress-induced human corneal epithelial cells, which requires activation and formation of Bcl-3/p50 complex through a noncanonical NF-κB pathway.
    PLoS ONE 08/2011; 6(8):e23984. DOI:10.1371/journal.pone.0023984 · 3.23 Impact Factor
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    • "Importantly, and in concordance with the patient data, we found that the induction of Bcl-3 by cytokines was associated with increased proliferation of myeloma cells. However, in line with the results from Brocke-Heidrich et al. (5), we could not show any effect on thymidine incorporation or apoptosis when down regulating Bcl-3 with siRNA in the INA-6 cell line (data not shown). These results are from only one cell line and further studies are needed to clarify the exact role of Bcl-3. "
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