Chronic restraint stress attenuates p53 function and promotes tumorigenesis

Zhaohui Feng, Lianxin Liu, Cen Zhang, Tongsen Zheng, Jiabei Wang, Meihua Lin, Yuhan Zhao, Xiaowen Wang, Arnold J. Levine, Wenwei Hu

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7013-7018
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number18
DOIs
StatePublished - May 1 2012

All Science Journal Classification (ASJC) codes

  • General

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