Attenuated response of p53 and p21 in primary cultures of human prostatic epithelial cells exposed to DNA-damaging agents.
Attenuated response of p53 and p21 in primary cultures of human prostatic epithelial cells exposed to DNA-damaging agents.
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发表时间：
1995-09
期刊：
影响因子：
11.2
通讯作者：
Theodore Girinsky;C. Koumenis;Thomas G. Graeber;D. Peehl;A. Giaccia
中科院分区：
文献类型：
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作者：
Theodore Girinsky;C. Koumenis;Thomas G. Graeber;D. Peehl;A. Giaccia
前列腺癌的多灶性起源提示肿瘤抑制途径中的泛器官缺陷。虽然p53基因的结构突变与晚期前列腺癌有关，但对腺癌起源的正常人前列腺上皮细胞中p53对基因毒性应激的反应知之甚少。我们发现，大多数（10/12）的上皮细胞培养物来源于根治性前列腺切除术标本的组织学正常组织未能表现出p53的积累，电离辐射。来自良性前列腺增生和原发性前列腺腺癌的上皮细胞培养物也未能积累p53对电离辐射的反应。与此相反，培养的前列腺基质细胞来源于正常，良性前列腺增生，或腺癌组织表现出3-9倍的诱导p53照射后1-3小时内。由于p53通过诱导细胞周期蛋白cdk抑制剂p21来调节细胞周期检查点，我们研究了电离辐射暴露后p21的积累和细胞周期阻滞。有一个例外，上皮细胞，没有显示增加p53或p21诱导没有表现出显着的G1-S期阻滞响应电离辐射，而基质细胞积累的p53和p21表现出大的细胞周期阻滞。这些结果表明，上皮和基质前列腺细胞的DNA损伤反应之间的功能差异，并建议一个可能的机制，前列腺上皮细胞积累遗传变异的易感性增加。
The multifocal origin of prostate cancer suggests a pan-organ defect in a tumor suppressor pathway. Although structural mutations in the p53 gene have been implicated in late-stage prostate cancer, little is known about the p53 response to genotoxic stress in normal human prostatic epithelial cells from which adenocarcinomas originate. We found that the majority (10 of 12) of epithelial cell cultures derived from histologically normal tissues of radical prostatectomy specimens failed to exhibit p53 accumulation in response to ionizing radiation. Epithelial cell cultures derived from benign prostatic hyperplasia and a primary prostatic adenocarcinoma also failed to accumulate p53 in response to ionizing radiation. In contrast, cultures of prostatic stromal cells derived from normal, benign prostatic hyperplasia, or adenocarcinoma tissues exhibited a 3-9-fold induction of p53 within 1-3 h after irradiation. Since p53 regulates a cell cycle checkpoint through the induction of the cyclin-cdk inhibitor p21, we examined p21 accumulation and cell cycle arrest following exposure to ionizing radiation. With one exception, epithelial cells that did not display increased p53 or p21 induction did not demonstrate a significant G1-S arrest in response to ionizing radiation, whereas stromal cells that accumulated p53 and p21 exhibited a large cell cycle arrest. These results indicate a functional difference between the DNA damage response of epithelial and stromal prostatic cells and suggest a possible mechanism for the increased susceptibility of prostatic epithelial cells to accumulate genetic alterations.