Influence of glutathione S-transferase pi and p53 expression on tumor frequency and spectrum in mice
Influence of glutathione S-transferase pi and p53 expression on tumor frequency and spectrum in mice
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DOI：
10.1002/ijc.20540
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发表时间：
2005-01-01
影响因子：
6.4
通讯作者：
Tew, KD
中科院分区：
文献类型：
--
作者：
Gate, L;Majumdar, RS;Tew, KD
谷胱甘肽S-转移酶pi（GSTpi）在肿瘤发展中的作用以前已经被提出;然而，这种酶在致癌作用中的确切功能仍然不清楚。GSTpi已被鉴定为通过与c-Jun N-末端激酶（JNK）相互作用并抑制c-Jun N-末端激酶（JNK）的细胞信号传导的调节剂。这种激酶又被描述为p53稳定性和转录活性的调节剂。为了研究GST π和p53之间可能的相互作用，我们将GST π缺陷动物与p53（-/-）小鼠杂交。双敲除动物是存活的，但在6个月龄内发生肿瘤;然而，这些动物的寿命与GST π（+/-）/p53（-/-）和GST π（+/+）/p53（-/-）的寿命相似。p53杂合子小鼠的寿命明显长于p53（-/-）动物，并且肿瘤的发生要晚得多，GSTpi的表达并没有显著改变动物的寿命。相反，在野生型p53背景下，GSTpi（-/-）小鼠比杂合和野生型动物发生肿瘤的频率显著更高，中位无肿瘤生存期短20周。此外，在p53（+/+）背景下，三分之一的GST π（-/-）动物发展为肺腺瘤，而少于10%的GST π（+/-）发展为和GST π（+/+）呈现这种肿瘤。GSTpi表达不改变肿瘤发生标志物如考克斯-2或响应佛波酯的鸟氨酸脱羧酶的表达。此外，GSTpi缺陷的小鼠胚胎成纤维细胞对H2 O2诱导的凋亡更敏感。P53（-/-）细胞，独立于GSTTr状态，更敏感的紫外线和其他DNA损伤剂比野生型对应。这些结果表明GSTpi可能在自发性肿瘤的发生中发挥保护作用。(C)2004 Wiley-Liss，Inc.
The role of glutathione S-transferase pi (GSTpi) in tumor development has been previously suggested; however the exact function of this enzyme in carcinogenesis remains unclear. GSTpi has been identified as a modulator of cell signaling by interacting with and inhibiting c-Jun N-terminal kinase (JNK). This kinase has been in turn described as a regulator of p53 stability and transcriptional activity. To study the possible interaction between GSTpi and p53, we crossed GSTpi-deficient animals with p53(-/-) mice. Double knock out animals were viable but developed tumors within 6 months of age; the life span of these animals was however similar to that of GSTpi(+/-)/p53(-/-) and GSTpi(+/+)/p53(-/-). Mice heterozygous for p53 lived significantly longer than the p53(-/-) animals and developed tumors much later, and the expression of GSTpi did not significantly modify the life span of the animals. In contrast, in a wild-type p53 background, GSTpi(-/-) mice developed tumors with a significantly higher frequency than heterozygous and wild-type animals with a median tumor free life span 20 weeks shorter. In addition, in p53(+/+) background, one third of the GSTpi(-/-) animals developed lung adenomas, while less than 10% of GSTpi(+/-) develo and GSTpi(+/+) presented such tumors. GSTpi expression did not alter the expression of tumorigenesis markers such as COX-2 or ornithine decarboxylase in response to phorbol ester. Furthermore, GSTpi-deficient mouse embryo fibroblasts were more sensitive to H2O2-induced apoptosis. P53(-/-) cells, independent of GSTTr status, were more sensitive to UV and other DNA damaging agents than their wild-type counterparts. These results suggest that GSTpi may play a protective role in the development of spontaneous tumors. (C) 2004 Wiley-Liss, Inc.