The Study of the Circadian Rhythm in p53 Signaling

p53 信号转导的昼夜节律研究

• 批准号: 8519363
• 负责人: LONING None FU
• 金额: $ 27.37万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519363
• 关键词: ATM activation; Animal Model; Apoptosis; Biological; Brain; Cell Culture Techniques; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell physiology; Circadian Rhythms; Coupled; Cues; DNA Damage; Development; Diagnostic Neoplasm Staging; Feedback; Genes; Genetic; Genome Stability; Goals; Hormones; Human; Hypothalamic structure; Incidence; Lead; Lesion; Life Style; Link; Malignant - descriptor; Malignant Neoplasms; Mammals; Mediating; Metabolism; Mitosis; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Neoplasms; Nuclear; Oncogenic; Output; Pathway interactions; Periodicity; Peripheral; Physiological; Physiological Processes; Population; Post-Translational Protein Processing; Protein p53; Radiation; Reporting; Research; Rodent; Role; Signal Pathway; Signal Transduction; Societies; Sympathetic Nervous System; Testing; Time; Tissues; Tumor Suppression; Tumor Suppressor Genes; Tumor stage; c-myc Genes; cancer prevention; cancer therapy; circadian behavioral rhythms; circadian pacemaker; extracellular; human tissue; in vivo; loss of function; novel therapeutics; public health relevance; research study; response; senescence; tumor; tumorigenesis

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. PUBLIC HEALTH RELEVANCE: 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.

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。昼夜节律的破坏会导致动物模型和人类的肿瘤发展增加。哺乳动物生物钟由昼夜节律基因的反馈环路操作，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。 我们之前曾报道过，c-myc 和 p53 的表达遵循体内昼夜节律，昼夜节律基因、Period1 和 2 功能丧失，导致小鼠肿瘤生长和 DNA 损伤反应失调。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来引导细胞周期和外周时钟，交感神经系统通过激活Period1和2、Ap1-myc和ATM-p53信号同时激活外周时钟、细胞周期时钟和p53。昼夜节律的破坏会导致中枢和外周生物钟不同步，并解开 p53 和 Myc 信号传导，导致致癌 Myc 激活、不受控制的细胞增殖和肿瘤发展增加。 在此应用中，我们建议结合分子、细胞和遗传方法来研究 ATM-p53 信号传导的昼夜节律控制的机制和生物学意义。具体来说，我们将重点定义 1) 外设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的作用，通过控制相互作用的信号通路来激活外周时钟和 ATM； 3) 通过扰乱昼夜行为节律而解除 ATM-p53 信号传导的机制，以及通过昼夜节律门控一天中特定时间的 ATM-p53 激活来减少辐射引起的宿主组织损伤的可能性。 公共卫生相关性：在工业化社会中，生活方式的改变导致约 50% 的人口的内源性昼夜节律频繁受到破坏，从而导致全球癌症发病率增加。我们计划研究生物钟如何控制肿瘤抑制因子 p53 的表达，p53 在大多数类型的人类癌症中都失调或突变。我们的研究将有助于更好地了解癌症的机制，并开发癌症预防和治疗的新治疗策略。