Expression of prostate specific antigen (PSA) is negatively regulated by p53

被引:44
作者
Gurova, KV
Roklin, OW
Krivokrysenko, VI
Chumakov, PM
Cohen, MB
Feinstein, E
Gudkov, AV
机构
[1] Cleveland Clin Fdn, Dept Mol Biol NC20, Lerner Res Inst, Cleveland, OH 44195 USA
[2] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA
[3] Quark Biotech Inc, Pleasonton, CA 94566 USA
关键词
prostate specific antigen; p53; transcription; prostate cancer;
D O I
10.1038/sj.onc.1205001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 trychostatin 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.
引用
收藏
页码:153 / 157
页数:5
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