Timed somatic deletion of p53 in mice reveals age-associated differences in tumor progression.
Timed somatic deletion of p53 in mice reveals age-associated differences in tumor progression.
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DOI：
10.1371/journal.pone.0006654
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发表时间：
2009-08-14
期刊：
影响因子：
3.7
通讯作者：
Donehower LA
中科院分区：
文献类型：
--
作者：
Hinkal G;Parikh N;Donehower LA
p53 肿瘤抑制基因的失活突变经常发生在人类癌症的进展过程中。 p53 通过抗增殖作用（包括诱导细胞凋亡或衰老）抑制新生癌细胞的生长。为了在新的实验环境中测试 p53 肿瘤抑制功能，我们在不同年龄的小鼠的多个组织中体细胞删除了两个 p53 等位基因。与 6 月龄和 12 月龄时删除 p53 的小鼠相比，3 月龄时纯合删除 p53 的小鼠表现出更长的肿瘤潜伏期。这些结果与组织随着年龄的增长而积累致癌激活细胞的模型一致，并且这些细胞受到野生型 p53 的控制。我们还在用电离辐射 (IR) 治疗小鼠之前、同时和之后删除了 p53。 IR 治疗期间 p53 的缺失或存在对辐射诱导的淋巴瘤潜伏期没有影响，这证实了立即的 p53 损伤反应与癌症预防无关。即使野生型 p53 在 IR 后长达 4 周的存在也无法预防早期淋巴瘤的发生，这表明功能性 p53 的长期维持对于预防癌症的出现至关重要。这些实验表明，持续的p53抗癌功能充当最后或接近最后的防线，防止致癌激活的细胞进展为恶性肿瘤。
Inactivating mutations in the p53 tumor suppressor gene occur often in the progression of human cancers. p53 inhibits the outgrowth of nascent cancer cells through anti-proliferative actions (including induction of apoptosis or senescence). To test p53 tumor suppressor functions in a novel experimental context, we somatically deleted both p53 alleles in multiple tissues of mice at various ages. Mice homozygously deleted for p53 at 3 months of age showed a longer tumor latency compared to mice deleted for p53 at 6 and 12 months of age. These results are consistent with a model in which tissues accumulate oncogenically activated cells with age and these are held in check by wildtype p53. We also deleted p53 before, concurrent with, and after treatment of mice with ionizing radiation (IR). The absence or presence of p53 during IR treatment had no effect on radiation-induced lymphoma latency, confirming that the immediate p53 damage response was irrelevant for cancer prevention. Even the presence of wildtype p53 for up to four weeks post-IR provided no protection against early lymphoma incidence, indicating that long term maintenance of functional p53 is critical for preventing the emergence of a cancer. These experiments indicate that sustained p53 anti-oncogenic function acts as a final or near final line of defense preventing progression of oncogenically activated cells to malignant tumors.
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影响因子：
4.6
作者：
Hameyer, Dorothe;Loonstra, Ate;Bockamp, Ernesto
通讯作者：
Bockamp, Ernesto
影响因子：
8
作者：
Fukasawa, K;Wiener, F;Mai, SB
通讯作者：
Mai, SB
影响因子：
10.5
作者：
Maier, B;Gluba, W;Scrable, H
通讯作者：
Scrable, H
影响因子：
56.9
作者：
Fukasawa, K;Choi, T;VandeVoude, GF
通讯作者：
VandeVoude, GF
DOI：
10.1073/pnas.0708043104
发表时间：
2007-10-16
影响因子：
11.1
作者：
Feng, Zhaohui;Hu, Wenwei;Levine, Arnold J.
通讯作者：
Levine, Arnold J.