Overexpression of human O6-alkylguanine DNA alkyltransferase (AGT) prevents MNU induced lymphomas in heterozygous p53 deficient mice
Overexpression of human O6-alkylguanine DNA alkyltransferase (AGT) prevents MNU induced lymphomas in heterozygous p53 deficient mice
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DOI：
10.1038/sj.onc.1204700
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发表时间：
2001-08-30
期刊：
影响因子：
8
通讯作者：
Gerson, SL
中科院分区：
文献类型：
--
作者：
Reese, JS;Allay, E;Gerson, SL
O-6-烷基鸟嘌呤DNA烷基转移酶(AGT)是通过清除O-6-甲基鸟嘌呤(O(6)mg)加合物来预防MNU诱导的恶性转化的关键机制。我们询问杂合子P53缺失小鼠(P53+/-)是否比野生型小鼠更易患MNU诱导的淋巴瘤，以及O(6)镁加合物是否与这种易感性有关。为了确定MGMT过表达是否具有保护作用，将p53+/-小鼠培育成人MGMT转基因小鼠(MGMT+)，并给予50 mg/kg MNU治疗。MNU使非转基因p53+/-小鼠的胸腺淋巴瘤发生率从23%(n=13)增加到68%(n=22)，并将平均潜伏期从433天缩短到106天(与未治疗的小鼠相比P=0.01)。野生型小鼠MNU后发生率为30%(n=38)，平均潜伏期为135天。P53+/-小鼠胸腺过表达mGMT可使淋巴瘤发生率从68%降至28%(n=17)，潜伏期从106天延长至167天(P=0.003)。同样，MGMT+/野生型小鼠的淋巴瘤发生率从30%下降到8%(n=12)，潜伏期增加到297天(P=0.2)。在发生在P53+/-小鼠中的17例淋巴瘤中，仅2例发现野生型等位基因丢失，且未发现P53基因第5-8外显子的显著点突变。此外，在这些小鼠中没有P53功能的丧失。这些数据表明，未修复的O(6)mg损伤与减少的p53剂量协同作用，并导致p53+/-小鼠的淋巴肿大，但AGT过表达和快速去除O(6)mg加合物是有保护作用的。
O-6-alkylguanine DNA alkyltransferase (AGT) is a key mechanism in the prevention against MNU induced malignant transformation by removal of O-6 methyl guanine (O(6)mG) adducts. We asked whether heterozygous p53 deficient mice (p53+/-) would be more susceptible to MNU induced lymphomas than wild type mice, and whether O(6)mG adducts were responsible for this susceptibility. To determine whether MGMT overexpression would be protective, p53+/- mice were bred to human MGMT transgenic mice (MGMT+) and treated with 50 mg/kg MNU. MNU increased the incidence of thymic lymphomas in non-transgenic p53 + / - mice from 23% (n = 13) to 68% (n = 22) and decreased the mean latency from 433 to 106 days (P=0.01 compared to untreated mice). Wild type mice had an incidence of 30% (n = 38) and a mean latency of 135 days after MNU. Overexpression of MGMT in the thymus of p53 + / - mice significantly reduced the lymphoma incidence from 68 to 28% (n = 17) and increased the latency from 106 to 167 days (P=0.003). Similarly, the lymphoma incidence in MGMT + /wild type mice decreased from 30 to 8% (n = 12) and the latency increased to 297 days (P=0.2). Loss of the wild type allele was found in only 2/17 lymphomas occurring in p53 + / - mice and there were no significant point mutations in exons 5-8 of p53. Furthermore, there was no loss of p53 function in these mice. These data demonstrate that unrepaired O(6)mG lesions act cooperatively with the reduced p53 dose and lead to lymphomagenesis in p53+/- mice, but AGT overexpression and rapid removal of O(6)mG adducts is protective.