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PLoS One. 2010 Jun 7;5(6):e10995. doi: 10.1371/journal.pone.0010995.

Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice.

Author information

1
Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, United States of America.

Abstract

BACKGROUND:

Cell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Period1 and 2 (Per) or Cryptochrome1 and 2 (Cry) are deficient in cell cycle regulation and Per2 mutant mice are cancer-prone. However, it remains unclear how circadian rhythm in cell proliferation is generated in vivo and why disruption of circadian rhythm may lead to tumorigenesis.

METHODOLOGY/PRINCIPAL FINDINGS:

Mice lacking Per1 and 2, Cry1 and 2, or one copy of Bmal1, all show increased spontaneous and radiation-induced tumor development. The neoplastic growth of Per-mutant somatic cells is not controlled cell-autonomously but is dependent upon extracellular mitogenic signals. Among the circadian output pathways, the rhythmic sympathetic signaling plays a key role in the central-peripheral timing mechanism that simultaneously activates the cell cycle clock via AP1-controlled Myc induction and p53 via peripheral clock-controlled ATM activation. Jet-lag promptly desynchronizes the central clock-SNS-peripheral clock axis, abolishes the peripheral clock-dependent ATM activation, and activates myc oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice.

CONCLUSIONS/SIGNIFICANCE:

Tumor suppression in vivo is a clock-controlled physiological function. The central circadian clock paces extracellular mitogenic signals that drive peripheral clock-controlled expression of key cell cycle and tumor suppressor genes to generate a circadian rhythm in cell proliferation. Frequent disruption of circadian rhythm is an important tumor promoting factor.

PMID:
20539819
PMCID:
PMC2881876
DOI:
10.1371/journal.pone.0010995
[Indexed for MEDLINE]
Free PMC Article

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