Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer.
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.
Catz
S D
SD
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, CA 92037, USA.
Johnson
J L
JL
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000728:Androgens / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D016384:Consensus Sequence; D018983:DNA Footprinting; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D019281:Dimerization; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D019254:Genes, bcl-2; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins; D008297:Male; D016297:Mutagenesis, Site-Directed; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000473:pathology; D009570:Nitriles; D009930:Organic Chemicals; D010446:Peptide Fragments / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D021122:Protein Subunits; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction; D013450:Sulfones; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000728:Androgens; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009570:Nitriles; D009930:Organic Chemicals; D010446:Peptide Fragments; D021122:Protein Subunits; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha