The Study of the Circadian Rhythm in p53 Signaling

描述（由申请人提供）：在哺乳动物中，生物钟控制着体内的大多数细胞过程，包括细胞增殖。昼夜节律的破坏导致动物模型和人类肿瘤发展的增加。哺乳动物的生物钟由昼夜节律基因的反馈回路控制，由下丘脑的中央时钟、昼夜节律输入和输出通路以及所有研究组织中的外周时钟组成。我们之前报道过c-myc和p53在体内的表达遵循昼夜节律，昼夜节律基因Period1和2的功能丧失导致小鼠肿瘤生长和DNA损伤反应失控。最近，我们发现中枢时钟可以通过控制交感神经系统的昼夜节律，同时通过激活Period1和2、Ap1-myc和ATM-p53信号激活外周时钟、细胞周期时钟和p53，从而操纵细胞周期时钟和外周时钟。昼夜行为节律的破坏使中枢和外周时钟不同步，使p53和Myc信号不偶联，导致致癌Myc激活，细胞增殖不受控制，肿瘤发展增加。在这个应用中，我们建议采用分子、细胞和遗传相结合的方法来研究ATM-p53信号昼夜节律控制的机制和生物学意义。具体来说，我们将重点定义1)外围时钟在控制ATM激活响应交感信号中的直接和间接作用；2)交感神经信号通过控制相互作用的信号通路，作为激活外周时钟和ATM的昼夜时间线索；3)通过破坏昼夜行为节律来解除ATM-p53信号的机制，以及通过在一天中的特定时间激活昼夜节律门控ATM-p53来减少辐射诱导的宿主组织损伤的可能性。

DESCRIPTION (provided by applicant): 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.