Effect of p53 activation on cell growth, thymidine kinase-1 activity, and 3′-deoxy-3′-fluorothymidine uptake
Effect of p53 activation on cell growth, thymidine kinase-1 activity, and 3′-deoxy-3′-fluorothymidine uptake
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DOI：
10.1016/j.nucmedbio.2004.01.002
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发表时间：
2004-05-01
影响因子：
3.1
通讯作者：
Krohn, KA
中科院分区：
文献类型：
--
作者：
Schwartz, JL;Tamura, Y;Krohn, KA
使用胸苷（TdR）和胸苷类似物如3 '-脱氧-3'-氟胸苷（FLT）作为基于正电子发射断层扫描（PET）的肿瘤增殖率示踪剂是基于以下假设：测量这些核苷的摄取（主要是胸苷激酶-1（TK 1）活性的功能）提供了肿瘤中细胞增殖的准确测量。肿瘤生长受到许多因素的影响，包括肿瘤内的氧浓度以及肿瘤细胞是否暴露于细胞毒性疗法。p53基因在这两种条件下调节生长中起重要作用。本研究的目的是研究p53激活对细胞生长、TK 1活性和FLT摄取的影响。为了实现这一点，TK 1活性，S期分数，和FLT的摄取测定在平台期和指数生长培养的一对等基因的人肿瘤细胞系，其中p53的表达是正常的或灭活的人乳头瘤病毒16型E6的表达。电离辐射暴露用于刺激p53活性并诱导细胞周期进程的改变。我们发现，暴露于电离辐射的细胞诱导剂量依赖性的变化，在两个细胞系的细胞周期进程。在p53正常细胞系中，S期百分比、TK 1活性和FLT摄取之间的关系基本上没有变化。相反，TK 1活性和FLT摄取在p53缺陷的变体中保持高水平，即使由于p53依赖性G2阻滞而导致S期百分比较低。我们的结论是，一个功能性p53反应是必要的，以维持正常的关系TK 1活性和S期百分比辐射暴露后。(C)2004年爱思唯尔公司All rights reserved.
The use of thymidine (TdR) and thymidine analogs Such as 3'-deoxy-3'-fluorothymidine (FLT) as positron emission tomography (PET)-based tracers of tumor proliferation rate is based on the hypothesis that measurement of uptake of these nucleosides, a function primarily of thymidine kinase-1 (TK1) activity, provides an accurate measure of cell proliferation in tumors. Tumor growth is influenced by many factors including the oxygen concentration within tumors and whether tumor cells have been exposed to cytotoxic therapies. The p53 gene plays an important role in regulating growth under both of these conditions. The goal of this study was to investigate the influence of p53 activation on cell growth, TK1 activity, and FLT uptake. To accomplish this, TK1 activity, S phase fraction, and the uptake of FLT were determined in plateau-phase and exponentially growing cultures of an isogenic pair of human tumor cell lines in which p53 expression was normal or inactivated by human papilloma virus type 16 E6 expression. Ionizing radiation exposure was used to Stimulate p53 activity and to induce alterations in cell cycle progression. We found that exposure of cells to ionizing radiation induced dose-dependent changes in cell cycle progression in both cell lines. The relationship between S phase percentage, TK1 activity, and FLT uptake were essentially unchanged in the p53-normal cell line. In contrast, TK1 activity and FLT uptake remained high in the p53-deficient variant even when S phase percentage was low due to a p53-dependent G2 arrest. We Conclude that a functional p53 response is required to maintain the normal relationship between TK1 activity and S phase percentage following radiation exposure. (C) 2004 Elsevier Inc. All rights reserved.