Expression of prostate specific antigen (PSA) is negatively regulated by p53
Expression of prostate specific antigen (PSA) is negatively regulated by p53
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DOI：
10.1038/sj.onc.1205001
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发表时间：
2002-01-03
期刊：
影响因子：
8
通讯作者：
Gudkov, AV
中科院分区：
文献类型：
--
作者：
Gurova, KV;Roklin, OW;Gudkov, AV
虽然前列腺特异性抗原（PSA）被认为是一种独特的重要肿瘤标志物，并被广泛用于前列腺癌的早期检测，但其在肿瘤中表达升高的分子机制尚不清楚。通过使用cDNA微阵列基因表达谱，我们发现前列腺癌细胞系LNCaP中PSA mRNA水平增加了四倍，其中p53通路被显性负性p53突变体抑制。同样，p53抑制导致培养基中PSA蛋白分泌增加4-8倍，表明PSA基因表达受p53负控制。而野生型p53强烈抑制，显性负性p53突变体刺激PSA启动子驱动的转录和分泌的PSA在瞬时转染实验。野生型p53的抑制作用是不可检测的trychostatin A的存在下，表明组蛋白脱乙酰化参与PSA启动子活性的负调控。因此，PSA可能是前列腺细胞中转化相关p53抑制的组织特异性指标。这一发现为晚期前列腺癌PSA水平频繁升高提供了合理的解释。
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.