DNA Damage Recognition via Activated ATM and p53 Pathway in Nonproliferating Human Prostate Tissue
DNA Damage Recognition via Activated ATM and p53 Pathway in Nonproliferating Human Prostate Tissue
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DOI：
10.1158/0008-5472.can-10-0937
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Laiho, Marikki
中科院分区：
文献类型：
--
作者：
Jaamaa, Sari;af Hallstrom, Taija M.;Laiho, Marikki
DNA损伤反应（DDR）途径已在癌细胞系和小鼠模型中得到广泛研究，但对非恶性、缓慢复制的人体组织中不同细胞类型如何识别DNA损伤知之甚少。在这里，我们评估，使用离体培养的人前列腺组织，DDR引起的细胞毒性药物（喜树碱，阿霉素，依托泊苷，顺铂）和电离辐射（IR）的背景下，正常组织结构。使用基底和腔上皮细胞的特异性标志物，我们确定和量化细胞隔室特异性损伤识别。IR、阿霉素和依托泊苷诱导Ser（139）上的H2 AX磷酸化（γ H2 AX）和DNA损伤灶形成。令人惊讶的是，与基底细胞相比，腔上皮细胞在IR后缺乏显著的γ H2 AX反应，尽管在两种细胞类型中可以清楚地检测到Ser（1981）和53 BP 1灶上的ATM磷酸化。减弱的γ H2 AX反应似乎是由低水平的总H2 A引起的。腔细胞中的X。仅在对喜树碱和多柔比星的反应中检测到激活的ATM通路的下游靶点p53的显著增加。这些发现强调了在缓慢复制的组织中由DNA损伤激活的途径的多样性，并揭示了前列腺腔室中可能与前列腺肿瘤发生相关的意想不到的偏差。DDR中组织和细胞类型差异的详细映射将提供对治疗策略的相关反应的展望。Cancer Res; 70（21）; 8630-41.（C）2010年AACR。
DNA damage response (DDR) pathways have been extensively studied in cancer cell lines and mouse models, but little is known about how DNA damage is recognized by different cell types in nonmalignant, slowly replicating human tissues. Here, we assess, using ex vivo cultures of human prostate tissue, DDR caused by cytotoxic drugs (camptothecin, doxorubicin, etoposide, and cisplatin) and ionizing radiation (IR) in the context of normal tissue architecture. Using specific markers for basal and luminal epithelial cells, we determine and quantify cell compartment-specific damage recognition. IR, doxorubicin, and etoposide induced the phosphorylation of H2A.X on Ser(139) (gamma H2AX) and DNA damage foci formation. Surprisingly, luminal epithelial cells lack the prominent gamma H2AX response after IR when compared with basal cells, although ATM phosphorylation on Ser(1981) and 53BP1 foci were clearly detectable in both cell types. The attenuated gamma H2AX response seems to result from low levels of total H2A. X in the luminal cells. Marked increase in p53, a downstream target of the activated ATM pathway, was detected only in response to camptothecin and doxorubicin. These findings emphasize the diversity of pathways activated by DNA damage in slowly replicating tissues and reveal an unexpected deviation in the prostate luminal compartment that may be relevant in prostate tumorigenesis. Detailed mapping of tissue and cell type differences in DDR will provide an outlook of relevant responses to therapeutic strategies. Cancer Res; 70(21); 8630-41. (C)2010 AACR.