|Lee, Susie -|
|Donehower, Lawrencea -|
|Herron, Alan -|
|Moore, David -|
|Fu, Loning -|
Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 11, 2010
Publication Date: June 7, 2010
Citation: Lee, S., Donehower, L., Herron, A.J., Moore, D.D., Fu, L. 2010. Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice. Available: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010995 Interpretive Summary: Recent studies have revealed that disruption of circadian rhythm increases tumor development in both humans and animal models. However, it remains unclear why disruption of circadian rhythm may lead to tumorigenesis. We have found recently, that the circadian clock controls the homeostasis of cell proliferation by regulating the activities of key tumor suppressors over a 24 hour period. Loss of function circadian genes in peripheral tissues, or disruption of circadian rhythm by jet-lag both disrupts the homeostasis of extracellular signaling, abolishes the circadian rhythm in cell proliferation, and induces tumor development in mice. Our studies indicate that tumor suppression in vivo is a clock-controlled physiological function, and that frequent disruption of circadian rhythm should be considered as an important tumor promoting factor.
Technical Abstract: 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 Period 1 and 2 (Per) or Cryptochrome 1 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.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. Jetlag promptly desynchronizes the central clock-sympatric nerve system -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 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.