The Study of the Circadian Rhythm in p53 Signaling

描述（由申请人提供）：在哺乳动物中，生物钟控制体内大多数细胞过程，包括细胞增殖。昼夜节律的破坏导致动物模型以及人类中肿瘤发展的增加。哺乳动物的昼夜节律钟是由昼夜节律基因的反馈回路控制的，它由下丘脑的中枢时钟、昼夜节律输入和输出通路以及所研究的所有组织中的外周时钟组成。 我们以前曾报道过，c-myc和p53的表达遵循体内的昼夜节律，昼夜节律基因，周期1和2的功能丧失，导致肿瘤生长和失调的DNA损伤反应在小鼠中。近年来，我们发现中枢生物钟可以通过控制交感神经系统的昼夜节律性，同时通过激活Period 1和2、Ap 1-myc和ATM-p53信号通路，激活外周生物钟、细胞周期生物钟和p53，从而影响细胞周期和外周生物钟。昼夜行为节律的破坏使中枢和外周生物钟失活，并使p53和Myc信号传导解偶联，导致致癌Myc激活、不受控制的细胞增殖和增加的肿瘤发展。 在本申请中，我们建议使用分子、细胞和遗传学方法的组合来研究ATM-p53信号传导的昼夜节律控制的机制和生物学意义。具体而言，我们将集中于定义1）外周时钟在响应交感神经信号控制ATM激活中的直接和间接作用：2）交感神经信号作为昼夜节律时间线索通过控制相互作用的信号通路激活外周时钟和ATM的作用;以及3）通过破坏昼夜行为节律来解除ATM-p53信号转导的机制和通过昼夜门控ATM-p53来减少辐射诱导的宿主组织损伤的可能性。p53在一天中的特定时间激活。

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.