Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer

Oncogene. 2001 Nov 1;20(50):7342-51. doi: 10.1038/sj.onc.1204926.


This work presents direct evidence that the bcl-2 gene is transcriptionally regulated by nuclear factor-kappa B (NF-kappa B) and directly links the TNF-alpha/NF-kappa B signaling pathway with Bcl-2 expression and its pro-survival response in human prostate carcinoma cells. DNase I footprinting, gel retardation and supershift analysis identified a NF-kappa B site in the bcl-2 p2 promoter. In the context of a minimal promoter, this bcl-2 p2 site 1 increased transcription 10-fold in the presence of the p50/p65 expression vectors, comparable to the increment observed with the consensus NF-kappa B site, while for the full p2 promoter region transcriptional activity was increased sixfold by over-expression of NF-kappa B, an effect eliminated by mutating the bcl-2 p2 site 1. The expression of Bcl-2 has been linked to the hormone-resistant phenotype of advanced prostate cancer. Here we show that an increase in the level of expression of Bcl-2 in the human prostate carcinoma cell line LNCaP observed in response to hormone withdrawal is further augmented by TNF-alpha treatment, and this effect is abated by inhibitors of NF-kappa B. Concomitantly, bcl-2 p2 promoter studies in LNCaP cells show a 40-fold increase in promoter activity after stimulation with TNF-alpha in the absence of hormone.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Androgens* / pharmacology
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Consensus Sequence
  • DNA Footprinting
  • DNA-Binding Proteins / antagonists & inhibitors
  • Dimerization
  • Gene Expression Regulation, Neoplastic / physiology*
  • Genes, bcl-2*
  • Genetic Vectors / genetics
  • Humans
  • I-kappa B Proteins*
  • Male
  • Mutagenesis, Site-Directed
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / chemistry
  • NF-kappa B / physiology*
  • Neoplasms, Hormone-Dependent / genetics*
  • Neoplasms, Hormone-Dependent / pathology
  • Nitriles*
  • Organic Chemicals*
  • Peptide Fragments / pharmacology
  • Promoter Regions, Genetic / genetics*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Protein Subunits
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Signal Transduction
  • Sulfones*
  • Transcriptional Activation*
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology


  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • Androgens
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nitriles
  • Organic Chemicals
  • Peptide Fragments
  • Protein Subunits
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfones
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha