Abstract
Although prostate-specific antigen (PSA) is considered a uniquely important tumor marker and is broadly used for early detection of prostate cancer, the molecular mechanisms underlying its elevated expression in tumors have been unknown. By using cDNA microarray gene expression profiling, we found a fourfold increase in the PSA mRNA level in prostatic carcinoma cell line LNCaP, in which the p53 pathway was suppressed by a dominant negative p53 mutant. Consistently, p53 suppression caused a 4-8-fold increase in secretion of PSA protein in culture medium, suggesting that PSA gene expression is under negative control of p53. While wild type p53 strongly repressed, dominant negative p53 mutants stimulated PSA promoter-driven transcription and secretion of PSA in transient transfection experiments. The inhibitory effect of wild type p53 was undetectable in the presence of trichostatin A, suggesting the involvement of histone deacetylation in negative regulation of PSA promoter activity. Thus, PSA is likely to be a tissue specific indicator of transformation-associated p53 suppression in prostate cells. This finding provides a plausible explanation for a frequent increase of PSA levels in advanced prostate cancer.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylation
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Adenocarcinoma / genetics*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Chloramphenicol O-Acetyltransferase / biosynthesis
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Chloramphenicol O-Acetyltransferase / genetics
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Culture Media, Conditioned
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DNA, Complementary / genetics
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Gene Expression Regulation, Neoplastic / physiology*
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Genes, Dominant
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Genes, Reporter
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Genes, p53
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Humans
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Hydroxamic Acids / pharmacology
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Male
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neoplasm Proteins / physiology*
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Oligonucleotide Array Sequence Analysis
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Promoter Regions, Genetic / genetics
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Prostate-Specific Antigen / biosynthesis*
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Prostate-Specific Antigen / genetics
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Prostate-Specific Antigen / metabolism
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Processing, Post-Translational
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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Recombinant Fusion Proteins / biosynthesis
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Transcription, Genetic
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Tumor Cells, Cultured / metabolism
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / physiology*
Substances
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Culture Media, Conditioned
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DNA, Complementary
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Hydroxamic Acids
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Neoplasm Proteins
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RNA, Messenger
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RNA, Neoplasm
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Recombinant Fusion Proteins
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Tumor Suppressor Protein p53
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trichostatin A
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Chloramphenicol O-Acetyltransferase
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Prostate-Specific Antigen