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: 8773710
• 负责人: DAVID A FOSTER
• 金额: $ 25.59万
• 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/8773710
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Address; Amino Acids; Apoptosis; Apoptotic; Cancer cell line; Cell Aging; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cells; Commit; Complement; Cyclin-Dependent Kinases; DNA; Dependence; Epigallocatechin Gallate; Essential Amino Acids; Essential Fatty Acids; Fostering; Genome; Glutamine; Growth Factor; 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; ethylisopropylamiloride; gallocatechol; human FRAP1 protein; mTOR protein; prevent; programs; public health relevance; 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）：人类癌症中的代谢细胞周期检查点失调的细胞决定分裂或进入静止的决定是在有丝分裂后早期在G1中进行的。细胞需要从生长因子中进行的指示，以继续通过G1循环到S期。在没有适当的生长因子信号的情况下，细胞进入静止的静止状态。 到G0。 G1中需要生长因子信号的地点已将其映射到G1早期的站点。该站点通常称为限制点（R）。但是，许多报告将R描述为G1中的一个站点，在该地点，该细胞最终承诺复制其DNA和分裂。该站点类似于酵母细胞周期中的一个站点，称为“开始”。但是，开始取决于营养足以而不是生长因素。我们提出了G1后期的一组代谢检查点，这些检查点取决于在承诺复制基因组和分裂之前的营养输入。 G1晚期的G1细胞周期控制位点可能被整合到MTOR介导的信号中，MTOR是雷帕霉素的哺乳动物靶标，它可以感知营养和能量。我们假设这些晚期的G1细胞周期控制位点共同代表了“细胞生长”检查点，在该检查点，在承诺将质量加倍并复制基因组之前，评估必需营养素的水平。有人提出，这些代谢检查点以及R几乎在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均配合以克服R和细胞生长检查点。这项研究解决了对G1细胞周期进程的长期误解，并研究了人类癌症中细胞周期检查点失调的治疗性剥削的可行性。该提案的中心假设是，G1后期有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。因此，细胞首先决定是否应在R上分裂，然后在复制基因组之前决定是否能够在监测营养足够的一组代谢细胞生长检查点上分裂。有人提出，MTOR是是否承诺复制基因组并分裂的最终仲裁者。提出了一系列实验：1）区分生长因子，营养和MTOR对G1细胞周期进程的影响 - 最重要的是，新近鉴定的脂质敏感的G1检查点； 2）区分细胞对G1细胞周期进展的要求，起源于有丝分裂或静止；和3）表征谷氨酰胺介导的细胞周期检查点，并评估人类癌细胞系中治疗性利用失调检查点的可行性。通过细胞周期的G1促进进展的许多信号通常被称为“生存信号”，因为它们抑制了如果细胞无法复制基因组和分裂的凋亡程序。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凋亡或衰老。这项研究将研究G1晚期的一组代谢检查点，这些检查点几乎通过所有癌细胞中的存活信号来克服。因此，这项研究将对大部分的人类癌症具有相关性和影响，因为需要通过G1晚期对进展的控制失调，并避免了预防癌症的细胞死亡和衰老程序。