Notch Mediated Intercellular Communication and Cell cycle Regulation

项目摘要 通过信号传导途径协调调节细胞增殖和分化是细胞增殖和分化的基础。 多细胞生物的发展。这些法规的失败往往导致 肿瘤发生或发育过程中的生长缺陷。Notch信号通路介导的 细胞间通讯对于正常细胞周期中广泛的生物过程是至关重要的。 许多人类疾病的发展和发病机制，包括多种类型的癌症。 然而，Notch与细胞周期调控和生长控制的关系是复杂的，因为Notch可以发挥作用， 肿瘤抑制或致癌作用。此外，很少有人知道是否和如何 细胞周期机制反馈以影响Notch信号传导。拟议的研究是基于两个 关于果蝇卵子发生模型系统中Notch调控的令人惊讶的初步发现， Notch在控制细胞周期程序从有丝分裂到有丝分裂的转换中起着核心作用。 在上皮滤泡细胞中的内复制周期。我们发现染色质组装因子1（CAF-1） 作为抑制因子和激活因子调节Notch靶基因在卵泡细胞中的表达。我们 还发现细胞周期机制调节Notch活性形式的稳定性，即细胞质中的Notch。 域NICD。在这些新发现的基础上，提出了两个具体目标，以确定（1） CAF-1调节Notch信号的分子机制和（2）潜在的反馈 Notch稳定性和活性的细胞周期机制。这两个目标都涉及重要的 Notch调节的一些方面与细胞增殖控制相关，但可以单独执行。的 该项目的成果将有助于更好地理解Notch信号传导和细胞 循环机制在动物发育和组织内稳态期间相互作用。新的见解， 在果蝇模型系统中调节Notch信号传导将对生物医学产生积极影响。 由于Notch通路与肿瘤发生和癌症的强相关性， 发展这些研究的结果将提供新的概念理解， 信号传导途径发挥其作用以确保细胞和组织生长中的正确决定， 这些理解可用于设计与异常Notch相关的疾病的新疗法 发信号。

PROJECT SUMMARY Coordinated regulation of cell proliferation and differentiation by signaling pathways is fundamental to the development of multicellular organisms. Failure in such regulations frequently lead to tumorigenesis or growth defects during development. The Notch signaling pathway mediated intercellular communication is critical for a wide range of biological processes during normal development and pathogenesis of numerous human diseases, including multiple types of cancer. However, its relationship with cell cycle regulation and growth control is complex since Notch can play either a tumor suppressor or an oncogenic role. Furthermore, little is known on whether and how the cell cycle machinery feeds back to influence Notch signaling. The proposed studies are based on two surprising preliminary findings on Notch regulation in the Drosophila oogenesis model system, where Notch plays a central role in controlling the switch of the cell cycle programs from mitosis to endoreplication cycles in epithelial follicle cells. We find that the Chromatin Assembly Factor 1 (CAF-1) acts as both a repressor and an activator to regulate Notch target gene expression in follicle cells. We also find that the cell cycle machinery regulates the stability of the active form of Notch, the cytoplasmic domain NICD. On the basis of these new findings, two specific aims are proposed to determine (1) the molecular mechanisms underlying CAF-1 regulation of Notch signaling and (2) the potential feedback mechanisms of the cell cycle machinery on Notch stability and activity. Both aims address important aspects of Notch regulation in relation to cell proliferation control, but can be executed separately. The outcomes of the proposed project will lead to improved understanding of how Notch signaling and cell cycle machinery interact during animal development and tissue homeostasis. The new insights into the regulation of Notch signaling in the Drosophila model system will have a positive impact on biomedical research due to the strong correlation of the Notch pathway with tumorigenesis and cancer development. The findings from these studies will provide new conceptual understandings of how signaling pathways exert their roles to ensure correct decisions in cellular and tissue growth, understandings which can be used to design novel therapies for diseases related to aberrant Notch signaling.