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: 8.56). 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Nonsense-mediated mRNA decay (NMD) limits the production of aberrant mRNAs containing a premature termination codon and also controls the levels of endogenous transcripts. Here we show that when human cells are treated with clinically used chemotherapeutic compounds, NMD activity declines partly as a result of the proteolytic production of a dominant-interfering form of the key NMD factor UPF1. Production of cleaved UPF1 functions to upregulate genes involved in the response to apoptotic stresses. The biological consequence is the promotion of cell death. Combined exposure of cells to a small-molecule inhibitor of NMD, NMDI-1, and the chemotherapeutic doxorubicin leads to enhanced cell death, while inhibiting UPF1 cleavage protects cells from doxorubicin challenge. We propose a model to explain why the expression levels of genes producing mRNAs of diverse structure that encode proteins of diverse function are under the purview of NMD.
    Nature Communications 03/2015; 6:6632. DOI:10.1038/ncomms7632 · 10.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although several pro-inflammatory cytokines including interleukin-6 (IL-6), IL-7, IL-12/IL-23, IL-17, IL-2, interferon, and the anti-inflammatory cytokines, IL-4/IL-13, IL-10, and IL-22, all activate the Janus kinase/signal transducers and activators of transcription (JAK/ STAT) pathway, in autoimmune disorders, a skewing of the cytokine repertoire in favor of pro-inflammatory cytokines results in amplifying the effects of pro-inflammatory cytokines. An apparent deficiency of anti-inflammatory cytokines to counterbalance the 'ramping up' of pro-inflammatory cytokine-mediated activation of JAK/STAT is also significant, while endog-enous negative regulators of cytokine signaling and JAK/STAT activation may also be com-promised. In addition, JAK/STAT pathway activation can result in activation of stress-activated protein/mitogen-activated protein kinase (SAP/MAPK) and phosphatidylinositol-3-kinase/ Akt/ mammalian target of rapamycin pathways that are instrumental in promoting matrix metal-loproteinase gene expression, aberrant cell survival, and osteoclast differentiation. The critical role played by pro-inflammatory cytokines in differentially activating JAK/STAT and parallel signal transduction pathways resulted in the development of several cytokine/cytokine receptor neutralizing monoclonal antibodies and fusion proteins that are currently employed for treating rheumatoid arthritis, Crohn's disease, and psoriasis. Small molecule inhibitors (SMIs) that target specific JAK enzymes have led to the development of CP690550, a JAK3-specific SMI, which is the first JAK-specific SMI to reach phase III in a rheumatoid arthritis clinical trial.
    International Journal of Interferon, Cytokine and Mediator Research 01/2010; DOI:10.2147/IJICMR.S9470
  • [Show abstract] [Hide abstract]
    ABSTRACT: The transcriptional regulator STAT3 curbs pro-inflammatory cytokine production mediated by NF-κB signalling in innate immune cells, yet the mechanism by which this occurs has been unclear. Here we identify STAT3 as a pivotal negative regulator of Ubc13, an E2 ubiquitin-conjugating enzyme that facilitates TRAF6 K63-linked ubiquitination and NF-κB activation. Ubc13 accumulates intracellularly in the absence of STAT3. Depletion of Ubc13 in Stat3-deficient macrophages subdues excessive RANKL- or LPS-dependent gene expression, indicating that Ubc13 overexpression mediates enhanced transcriptional responses in the absence of STAT3. In RANKL-activated macrophages, STAT3 is stimulated by autocrine IL-6 and inhibits accrual of Ets-1, Set1 methyltransferase and trimethylation of histone H3 lysine 4 (H3K4me3) at the Ube2n (Ubc13) promoter. These results delineate a mechanism by which STAT3 operates as a transcriptional repressor on Ube2n, thus modulating NF-κB activity by regulation of Ubc13 abundance. Our data suggest that this pathway plays important roles in bone homeostasis and restraint of inflammation.
    Nature Communications 01/2014; 5:5798. DOI:10.1038/ncomms6798 · 10.74 Impact Factor

Full-text (2 Sources)

Available from
Oct 8, 2014