Dysregulated Metabolic Cell Cycle Checkpoints in Human Cancer

人类癌症中代谢细胞周期检查点失调

• 批准号: 8910668
• 负责人: DAVID A FOSTER
• 金额: $ 25.76万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910668
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Address; Amiloride; Amino Acids; Apoptosis; Apoptotic; Cancer cell line; Cell Aging; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cells; Complement; Cyclin-Dependent Kinases; DNA; Dependence; Epigallocatechin Gallate; Essential Amino Acids; Essential Fatty Acids; Fostering; Genome; Glutamine; Growth Factor; Health; Human; Instruction; Lead; Lipids; Malignant Neoplasms; Mammalian Cell; Maps; Mediating; Metabolic; Mitosis; Monitor; Mutation; Normal Cell; Nutrient; Nutritional Requirements; Phosphatidic Acid; Phospholipase D; Phosphorylation; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Reporting; Rest; Running; S Phase; S Phase Arrest; Series; Signal Transduction; Sirolimus; Site; Staging; Therapeutic; Therapeutic Intervention; Transforming Growth Factors; Yeasts; cancer cell; cell growth; conditionally essential amino acid; detection of nutrient; gallocatechol; human FRAP1 protein; mTOR protein; prevent; programs; research study; senescence

DESCRIPTION (provided by applicant): Dysregulated Metabolic Cell Cycle Checkpoints in Human Cancer The decision by a cell to divide or enter quiescence is made in early G1 after mitosis. Cells need instructions from growth factors to continue cycling through G1 into S-phase. In the absence of appropriate growth factor signals, cells enter a resting quiescent state referred to as G0. The site in G1 where growth factor signals are required has been mapped to a site early in G1. This site is commonly referred to as the Restriction Point (R). However, many reports describe R as a site much later in G1 where the cell makes a final commitment to replicate its DNA and divide. This site resembles a site in the yeast cell cycle known as START. However, START is dependent upon nutrient sufficiency rather than growth factors. We are proposing a set of metabolic checkpoints late in G1 that are dependent on nutrient input prior to committing to replicate the genome and dividing. This late G1 cell cycle control site is likely integrated into signals mediated by mTOR - the mammalian target of rapamycin, which senses nutrient and energy sufficiency. We hypothesize that these late G1 cell cycle control sites collectively represent a "Cell Growth" checkpoint where levels of essential nutrients are evaluated prior to committing to doubling in mass and replicating the genome. It is proposed that these metabolic checkpoints, along with R, need to be dysregulated in virtually all human cancers and that complementary genetic changes in human cancer cells cooperate to overcome both R and the Cell Growth checkpoints. This study addresses long-running misconceptions about of G1 cell cycle progression and investigates the feasibility of therapeutic exploitation of dysregulated cell cycle checkpoints in human cancers. The Central Hypothesis of the proposal is that there are Metabolic Cell Cycle Checkpoints late in G1 that can be distinguished from the growth factor-dependent Restriction Point (R). Thus, cells decide first whether they should divide at R, and then prior to replicating the genome, they decide whether they are capable of dividing at a set of Metabolic Cell Growth checkpoints that monitor nutrient sufficiency. It is proposed that mTOR is the final arbiter of whether to commit to replicating the genome and dividing. A series of experiments are proposed that will: 1) Distinguish the impact of growth factors, nutrients and mTOR on G1 cell cycle progression - most significantly, a newly identified lipid-sensitive G1 checkpoint; 2) Distinguish requirements of cells for G1 cell cycle progression when originating from mitosis or from quiescence; and 3) Characterize cell cycle checkpoint(s) mediated by glutamine and evaluate the feasibility of therapeutically exploiting dysregulated checkpoints in human cancer cell lines. Many of the signals that promote progression through late G1 of the cell cycle are commonly referred to as "survival signals" because they suppress apoptotic programs that kick in if the cell is not capable of replicating the genome and dividing. These signals are ideal targets for therapeutic intervention because, in principle, suppression of survival signals leads to either apoptosis or senescence. This study will investigate a proposed set of Metabolic checkpoints in late G1 that are overcome by survival signals in virtually all cancer cells. Therefore, the study will have relevance - and impact - for a large percentage of human cancers because of the need to dysregulate the control of progression through late G1 and avoid the cell death and senescence programs that prevent cancer.

描述（由申请人提供）：人类癌症中代谢细胞周期检查点失调细胞分裂或进入静止的决定是在有丝分裂后的早期 G1 中做出的。细胞需要生长因子的指示才能继续从 G1 期进入 S 期。在缺乏适当的生长因子信号的情况下，细胞进入静息状态 为 G0。 G1 中需要生长因子信号的位点已被映射到 G1 早期的位点。该站点通常称为限制点 (R)。然而，许多报告将 R 描述为 G1 期较晚的一个位点，细胞在此做出最终的 DNA 复制和分裂决定。该位点类似于酵母细胞周期中称为 START 的位点。然而，START 取决于营养充足程度而不是生长因子。我们提出了一组 G1 后期的代谢检查点，这些检查点依赖于复制基因组和分裂之前的营养输入。这个晚期 G1 细胞周期控制位点可能整合到 mTOR 介导的信号中，mTOR 是哺乳动物雷帕霉素的靶标，可感知营养和能量充足度。我们假设这些晚期 G1 细胞周期控制位点共同代表了一个“细胞生长”检查点，在进行质量加倍和复制基因组之前，必须评估必需营养素的水平。有人提出，这些代谢检查点与 R 一起，在几乎所有人类癌症中都需要失调，并且人类癌细胞中的互补遗传变化协同克服 R 和细胞生长检查点。这项研究解决了长期以来对 G1 细胞周期进展的误解，并研究了人类癌症中细胞周期检查点失调的治疗利用的可行性。该提案的中心假设是，G1 晚期存在代谢细胞周期检查点，可以与生长因子依赖性限制点 (R) 区分开来。因此，细胞首先决定它们是否应该在 R 处分裂，然后在复制基因组之前，它们决定它们是否能够在一组监测营养充足性的代谢细胞生长检查点处分裂。有人提出mTOR是是否致力于复制基因组和分裂的最终仲裁者。提出了一系列实验，这些实验将：1）区分生长因子、营养素和 mTOR 对 G1 细胞周期进程的影响 - 最重要的是，新发现的脂质敏感 G1 检查点； 2）区分来自有丝分裂或静止时细胞对G1细胞周期进展的要求； 3) 表征由谷氨酰胺介导的细胞周期检查点，并评估利用人类癌细胞系中失调的检查点进行治疗的可行性。许多促进细胞周期 G1 晚期进展的信号通常被称为“生存信号”，因为它们会抑制细胞无法复制基因组和分裂时启动的细胞凋亡程序。这些信号是治疗干预的理想目标，因为原则上，抑制生存信号会导致细胞凋亡或衰老。这项研究将研究一组拟议的 G1 晚期代谢检查点，几乎所有癌细胞中的存活信号都可以克服这些检查点。因此，这项研究将对大部分人类癌症产生相关性和影响，因为需要调节 G1 晚期的进展控制，并避免预防癌症的细胞死亡和衰老程序。