Journal Article

Chronic restraint stress attenuates p53 function and promotes tumorigenesis

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

2012

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adverse effects / Animal models / Animals / Apoptosis / Apoptosis - drug effects / Biological Sciences / Brain / Cancer / carcinogenesis / Cell Line, Tumor / Cocarcinogenesis / Corticosterone / Corticosterone - pharmacology / deficiency / Disease Models, Animal / drug effects / epidemiological studies / etiology / Genes, p53 / genetics / Glucocorticoids / Glucocorticoids - metabolism / HCT116 cells / Heterologous transplantation / Humans / Hydrocortisone / Hydrocortisone - pharmacology / Immediate-Early Proteins / Immediate-Early Proteins - genetics / Immediate-Early Proteins - metabolism / Infrared radiation / Insulin resistance / Ionizing radiation / Kinases / Male / MDM2 protein / metabolism / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Knockout / Mice, Nude / Neoplasm Transplantation / Neoplasms, Radiation-Induced / Neoplasms, Radiation-Induced - etiology / p53 protein / pharmacology / physiology / Protein kinase / protein kinases / Protein Serine-Threonine Kinases / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Proteins / Proto-Oncogene Proteins c-mdm2 / Proto-Oncogene Proteins c-mdm2 - metabolism / psychological stress / Restraint, Physical / Restraint, Physical - adverse effects / Restraint, Physical - physiology / RNA, Messenger / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Spleen / Stress / Stress, Physiological / Transplantation, Heterologous / Tumor suppressor genes / Tumor Suppressor Protein p53 / Tumor Suppressor Protein p53 - deficiency / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - physiology / Tumorigenesis / Tumors / Xenografts