Chronic restraint stress attenuates p53 function and promotes tumorigenesis
Chronic restraint stress attenuates p53 function and promotes tumorigenesis
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DOI：
10.1073/pnas.1203930109
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发表时间：
2012-05-01
影响因子：
11.1
通讯作者：
Hu, Wenwei
中科院分区：
文献类型：
--
作者：
Feng, Zhaohui;Liu, Lianxin;Hu, Wenwei
流行病学研究强烈表明，慢性心理压力促进肿瘤发生。然而，其在体内的直接联系和导致这种情况的潜在机制仍不清楚。这项研究提供了直接的证据表明，慢性应激促进体内肿瘤发生;慢性束缚，一个成熟的小鼠模型，诱导慢性应激，大大促进电离辐射（IR）诱导的肿瘤发生在p53（+/-）小鼠。肿瘤抑制蛋白p53在肿瘤预防中起着重要作用。p53功能的缺失或减弱对肿瘤的发生有重要作用。我们发现，慢性束缚降低了小鼠中p53的水平和功能，并且以很大程度上依赖于p53的方式促进了人类异种移植肿瘤的生长。我们的研究结果表明，糖皮质激素在慢性约束期间升高介导慢性约束对p53的影响，通过诱导血清和糖皮质激素诱导的蛋白激酶（SGK1），这反过来又增加了MDM2的活性，降低p53的功能。总之，这项研究表明，慢性应激促进小鼠的肿瘤发生，p53功能的衰减是潜在机制的重要组成部分，这可以通过在慢性束缚期间升高的糖皮质激素介导。
Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause this remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well-established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in p53(+/-) mice. The tumor suppressor protein p53 plays a central role in tumor prevention. Loss or attenuation of p53 function contriubutes greatly to tumorigenesis. We found that chronic restraint decreases the levels and function of p53 in mice, and furthermore, promotes the growth of human xenograft tumors in a largely p53-dependent manner. Our results show that glucocorticoids elevated during chronic restraint mediate the effect of chronic restraint on p53 through the induction of serum-and glucocorticoid-induced protein kinase (SGK1), which in turn increases MDM2 activity and decreases p53 function. Taken together, this study demonstrates that chronic stress promotes tumorigenesis in mice, and the attenuation of p53 function is an important part of the underlying mechanism, which can be mediated by glucocortcoids elevated during chronic restraint.