Dysregulation of the mTOR pathway in p53-deficient mice
Dysregulation of the mTOR pathway in p53-deficient mice
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DOI：
10.4161/cbt.26947
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发表时间：
2013-12-01
影响因子：
3.6
通讯作者：
Blagosklonny, Mikhail V.
中科院分区：
文献类型：
--
作者：
Leontieva, Olga V.;Novototskaya, Liliya R.;Blagosklonny, Mikhail V.
哺乳动物或机制雷帕霉素靶点（mTOR）参与生长、衰老和包括癌症在内的年龄相关疾病。p53和mTOR之间存在广泛的串扰。在细胞培养中，p53以细胞类型依赖的方式抑制mTOR通路。缺乏p53的小鼠会产生促炎症和癌症。我们已经证明雷帕霉素延缓癌症和延长寿命，从而部分取代p53。在这里，我们发现mTOR活性的一个标志，磷酸化S6 (p-S6)，在p53缺陷小鼠的心脏中增加。此外，心脏p-S6与体重相关。此外，p53（-/-）小鼠轻度高胰岛素血症，并有IGF-1升高的趋势。辐射加剧了正常小鼠和p53（-/-）小鼠IGF-1水平的差异。值得注意的是，辐射诱导p53（+/+）和p53（-/-）小鼠肝脏（而不是心脏）的Thr-308 Akt磷酸化。同时，辐射降低了正常小鼠肝脏中的p-S6，这与p53对mTOR的负作用一致。我们的数据表明，mTOR的活性在p53（-/-）小鼠的一些组织中增加，但不是所有组织都增加，这与胰岛素和IGF-1水平增加的趋势有关。因此，缺乏p53可能会产生亲癌微环境，有利于癌症的发生。
Mammalian or mechanistic target of rapamycin (mTOR) is involved in growth, aging, and age-related diseases including cancer. There is an extensive cross talk between p53 and mTOR. In cell culture, p53 inhibits the mTOR pathway in a cell type-dependent manner. p53-deficient mice develop pro-inflammation and cancer. We have shown that rapamycin delayed cancer and extended lifespan, thus partially substituting for p53. Here we show that a marker of mTOR activity, phosphorylated S6 (p-S6), is increased in the hearts of p53-deficient mice. Furthermore, cardiac p-S6 correlated with body weight. Also, p53(-/-) mice were slightly hyperinsulinemic with a tendency to elevated IGF-1. Radiation exacerbated the difference between IGF-1 levels in normal and p53(-/-) mice. Noteworthy, radiation induced Thr-308 Akt phosphorylation in the livers (but not in the hearts) of both p53(+/+) and p53(-/-) mice. Simultaneously, radiation decreased p-S6 in the livers of normal mice, consistent with the negative effect of p53 on mTOR. Our data indicate that the activity of mTOR is increased in some but not all tissues of p53(-/-) mice, associated with the tendency to increased insulin and IGF-1 levels. Therefore, the absence of p53 may create oncophilic microenvironment, favoring cancer.