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

Oncogene. 2006 Nov 23;25(55):7297-304. doi: 10.1038/sj.onc.1209711. Epub 2006 May 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Cell Lymphoma 3 Protein
  • Base Sequence
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • DNA Primers
  • Enhancer Elements, Genetic*
  • Gene Silencing
  • Humans
  • Interleukin-6 / metabolism*
  • Introns*
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Protein Binding
  • Proto-Oncogene Proteins / biosynthesis*
  • STAT3 Transcription Factor / metabolism*
  • Transcription Factors / biosynthesis*
  • Transcription, Genetic*

Substances

  • B-Cell Lymphoma 3 Protein
  • BCL3 protein, human
  • DNA Primers
  • Interleukin-6
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • Transcription Factors