Chronic restraint stress attenuates p53 function and promotes tumorigenesis

Contributed by Arnold J. Levine, March 8, 2012 (sent for review January 18, 2012)
April 16, 2012
109 (18) 7013-7018

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.

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Acknowledgments

W.H. is supported by National Institutes of Health (NIH) Grant 1P30CA147892-01, Department of Defense Grant W81XWH-10-1-0435, CINJ new investigator award, and the Ellison Foundation. Z.F. is supported by NIH Grant 1R01CA143204-01 and the New Jersey Commission on Cancer Research (NJCCR). C.Z. is supported by a postdoctoral grant from NJCCR.

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Information & Authors

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Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 109 | No. 18
May 1, 2012
PubMed: 22509031

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Submission history

Published online: April 16, 2012
Published in issue: May 1, 2012

Acknowledgments

W.H. is supported by National Institutes of Health (NIH) Grant 1P30CA147892-01, Department of Defense Grant W81XWH-10-1-0435, CINJ new investigator award, and the Ellison Foundation. Z.F. is supported by NIH Grant 1R01CA143204-01 and the New Jersey Commission on Cancer Research (NJCCR). C.Z. is supported by a postdoctoral grant from NJCCR.

Authors

Affiliations

Zhaohui Feng1
Department of Radiation Oncology and
Lianxin Liu1
Key Laboratory of Hepatosplenic Surgery, First Affiliated Hospital of Harbin Medical University, Harbin 150086, China; and
Cen Zhang
Department of Radiation Oncology and
Tongsen Zheng
cDepartment of Pediatrics, Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903;
Jiabei Wang
cDepartment of Pediatrics, Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903;
Meihua Lin
Department of Radiation Oncology and
Yuhan Zhao
cDepartment of Pediatrics, Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903;
Xiaowen Wang
Department of Radiation Oncology and
Arnold J. Levine2 [email protected]
Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540
cDepartment of Pediatrics, Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903;

Notes

2
To whom correspondence may be addressed. E-mail: [email protected] or [email protected].
Author contributions: Z.F., L.L., A.J.L., and W.H. designed research; Z.F., L.L., C.Z., T.Z., J.W., M.L., Y.Z., X.W., and W.H. performed research; Z.F., L.L., A.J.L., and W.H. analyzed data; and Z.F., L.L., A.J.L., and W.H. wrote the paper.
1
Z.F. and L.L. contributed equally to this work.

Competing Interests

The authors declare no conflict of interest.

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    Chronic restraint stress attenuates p53 function and promotes tumorigenesis
    Proceedings of the National Academy of Sciences
    • Vol. 109
    • No. 18
    • pp. 6785-7126

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