Mechanisms controlling cell cycle exit upon terminal differentiation

末端分化通常伴随着细胞周期的永久退出，并且代表了 成年动物常见的细胞状态。然而，目前仍不清楚分化型肿瘤的增殖是如何被阻止的。 纸巾。这个项目的目标是确定终末分化信号如何影响细胞周期。 诱导稳定静止状态的机制，并研究这种状态在癌症中是如何被破坏的。在 这里提出的研究，我使用了遗传和生化方法的组合在果蝇和 哺乳动物细胞来描绘控制细胞周期退出的保守遗传路径。在K99期间 在这项资助的阶段，我研究了限制分化果蝇循环的冗余机制 组织，获得了与两种不同的哺乳动物细胞系合作的经验，这两种细胞系可以被诱导为 在体外分化，为未来细胞周期退出的研究，并致力于筛选识别基因，当 过表达或被RNAi抑制，使细胞周期失控，从而在以下情况下导致异位增殖 末端分化。这种基因通常会在末端分化时被激活或抑制，但 很可能在癌症中变得失控。在颁奖的Roo阶段，我将确定准确的 这些基因调节细胞周期的机制(目标1)和研究哺乳动物的作用 这些基因在正常和癌症哺乳动物细胞中的同源基因(AIM2)。我还将调查 利用遗传上位性工具在果蝇和果蝇中调节这些基因的信号通路 哺乳动物细胞(目标3)。这项工作将开始划定连接终点站的保存路径 与细胞周期控制的分化信号，并确定它们如何变得不受调控，从而导致 癌症。

Terminal differentiation is often coupled with permanent exit from the cell cycle and represents the most common cellular state in adult animals. Yet it remains unclear how proliferation is blocked in differentiated tissues. The goal of this project is to determine how terminal differentiation signals impinge on the cell cycle machinery to induce a stable quiescent state and investigate how this state is disrupted in cancer. In the research proposed here, I use a combination of genetic and biochemical approaches in Drosophila and mammalian cells to delineate the conserved genetic pathways that control cell cycle exit. During the K99 phase of this grant, I investigated the redundant mechanisms that limit cycling in differentiated Drosophila tissues, obtained experience working with 2 different mammalian cell lines that can be induced to differentiate in vitro for future studies of cell cycle exit, and worked on a screen to identify genes that when overexpressed or inhibited by RNAi, de-regulate the cell cycle to cause ectopic proliferation in contexts of terminal differentiation. Such genes would normally be activated or inhibited upon terminal differentiation, but likely become de-regulated in cancers. During the ROO phase of the award, I will determine the precise mechanisms by which these genes regulate the cell cycle (Aim 1) and examine the roles of mammalian orthologs of these genes in normal and cancerous mammalian cells (Aim2). I will also investigate the signaling pathways by which these genes are regulated, using genetic epistasis tools in both Drosophila and mammalian cells (Aim 3). Such work will begin to delineate the conserved pathways connecting terminal differentiation signals with cell cycle controls, and determine how they can become de-regulated leading to cancer.