In mammals, the circadian clock controls most cellular processes in vivo including cell proliferation. Disruption of circadian rhythms leads to increased tumor development in animal models as well as in humans. The mammalian circadian clock is operated by the feedback loops of the circadian genes and is composed of a central clock in hypothalamus, the circadian input and output pathways, and peripheral clocks in all tissues studied. We have reported previously that the expression of c-myc and p53 follows a circadian rhythm in vivo and loss of function in the circadian genes, Period1 and 2, leads to neoplastic growth and deregulated DNA damage response in mice. Recently, we discovered that the central clock can entrain cell cycle and peripheral clocks by controlling the circadian rhythmicity of the sympathetic nervous system that simultaneously activates peripheral clock, cell cycle clock and p53 via activating Period1 and 2, Ap1-myc and ATM-p53 signaling. Disruption of circadian behavioral rhythm desynchronizes the central and peripheral clocks and uncouples p53 and Myc signaling resulting in oncogenic Myc activation, uncontrolled cell proliferation, and increased tumor development. In this application, we propose to study the mechanism and biological significance of circadian control of ATM-p53 signaling using a combination of molecular, cellular and genetic approaches. Specifically, we will focus on defining 1) the direct and indirect role of the peripheral clock in controlling ATM activation in response to sympathetic signaling;2) the role of the sympathetic signaling as a circadian time cue to activate peripheral clock and ATM via controlling interacting signaling pathways;and 3) the mechanism of deregulation of ATM-p53 signaling by disruption of circadian behavioral rhythm and the possibility of reducing radiation- induced host tissue damage by circadian gating ATM-p53 activation at a specific time of a day.
In industrialized societies, changes in lifestyles lead to frequent disruption of endogenous circadian rhythm in about 50% of the human population, which contributes to increased cancer development world-wide. We plan to investigate how the clock controls the expression of the tumor suppressor p53, which is deregulated or mutated in most of types of human cancers. Our studies will lead to a better understanding of the mechanism of cancer and to the development of novel therapeutic strategies for cancer prevention and treatment.
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