Nutrient Sensing and Growth Control

营养感应和生长控制

• 批准号: 8517130
• 负责人: Donald E Ayer
• 金额: $ 31.63万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517130
• 关键词: Affect; Amino Acids; Automobile Driving; Bioenergetics; Breast; Carbon; Cell Nucleus; Cell division; Cells; Citric Acid Cycle; Complex; Data; Dependence; Down-Regulation; Environment; Feedback; Figs - dietary; Funding; Gene Expression; Genetic; Genetic Transcription; Glucose; Glucose Transporter; Glutamine; Glycolysis; Growth; Growth Factor; Homeostasis; Housing; Human; Lead; Malignant - descriptor; Malignant Neoplasms; Mammalian Cell; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular Profiling; Monitor; Nutrient; Oncogenes; Organelles; Outer Mitochondrial Membrane; Ovarian; Pathway interactions; Play; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Reaction; Regulation; Reporting; Repression; Role; Signal Pathway; Signal Transduction; Skeleton; Stimulus; Supporting Cell; Therapeutic Intervention; Thioredoxin; Transcription Coactivator; Transcription Repressor/Corepressor; Transcriptional Regulation; Tumor Suppressor Proteins; Up-Regulation; Work; aerobic glycolysis; breast tumorigenesis; cancer cell; cell growth; detection of nutrient; genetic regulatory protein; glucose uptake; growth promoting activity; hexokinase; interest; malignant breast neoplasm; meetings; mouse model; neoplastic cell; programs; promoter; protein expression; response; transcription factor; tumor; unpublished works

DESCRIPTION (provided by applicant): Cell growth and division requires the coordination of growth factor signaling and metabolic pathways. It is quite common that this coordination is deregulated in human malignancy. For example, ectopic activation of growth factor signaling pathways is ubiquitous in cancer and drives cell growth and division. Further, cancer cells also require an elevated supply of nutrients, e.g. glucose, glutamine and amino acids, to support their high growth and division rates. A prime example of nutrient deregulation in cancer is the oncogene-dependent upregulation of glucose transporters and glycolysis. The mTORC1 complex is one signaling node where these diverse stimuli converge and the activity of this growth-promoting complex is highest in cells with abundant nutrients and engaged growth factor signaling pathways. How nutrient availability and growth signals are coordinated at the transcriptional level is poorly understood, however, our studies on the MondoA:Mlx complex indicate a prominent role for this bHLHZip factor complex in this regard. MondoA is the primary glucose- regulated transcription factor in mammalian cells, yet signals from the mitochondrial TCA cycle also control MondoA transcriptional activity. Our published data show that high rates of glutaminolysis convert MondoA from a transcriptional activator to a transcriptional repressor. MondoA's downregulation of thioredoxin interacting protein (TXNIP) creates an environment that is permissive for both glucose uptake and glycolysis. The MondoA-TXNIP regulatory circuit further coordinates cell growth as the mTORC1 complex negatively regulates this circuit. This blockage of MondoA:Mlx transcriptional activity by mTORC1, likely contributes to mTORC1's well-documented function in driving glucose uptake and glycolysis. The importance of the MondoA-TXNIP regulatory circuit is underscored by its likely tumor suppressor function in both breast, ovarian, and potentially other cancers. In this application, we propose to study on how the MondoA:Mlx complex senses and responds to the TCA cycle intermediate a-ketoglutarate. We will also determine the transcriptional networks that are activated downstream of mitochondrial status and the dependence of these networks on MondoA. Next, we will determine how the transcriptional functions of MondoA:Mlx complexes are controlled by the mTORC1 complex and the breadth of this regulation. Finally, we will examine the role of the MondoA- TXNIP circuit as a growth/tumor suppressor in breast cancer using mouse models. These studies will lead to a deeper understanding of how diverse signals from growth factor signaling pathways, mitochondrial status and nutrient availability are integrated by the MondoA:Mlx complex. Given that the deregulation of these pathways is near universal in human malignancy, our hope is that this work will provide new avenues for therapeutic intervention in cancer.

描述（由申请人提供）：细胞生长和分裂需要生长因子信号和代谢途径的协调。这种协调在人类恶性肿瘤中是很常见的。例如，生长因子信号通路的异位激活在癌症中普遍存在，并驱动细胞生长和分裂。此外，癌细胞还需要大量的营养物质供应，如葡萄糖、谷氨酰胺和氨基酸，以支持它们的高速生长和分裂速度。癌症中营养失调的一个主要例子是癌基因依赖性葡萄糖转运蛋白和糖酵解的上调。mTORC1复合体是这些不同刺激汇聚的一个信号节点，在营养丰富和参与生长因子信号通路的细胞中，这种促进生长的复合体的活性最高。然而，我们对MondoA:Mlx复合体的研究表明，bHLHZip因子复合体在这方面发挥了突出的作用。MondoA是哺乳动物细胞中主要的葡萄糖调节转录因子，然而来自线粒体TCA循环的信号也控制着MondoA的转录活性。我们发表的数据表明，谷氨酰胺水解的高速率将MondoA从转录激活因子转化为转录抑制因子。MondoA对硫氧还蛋白相互作用蛋白（TXNIP）的下调创造了一个允许葡萄糖摄取和糖酵解的环境。MondoA-TXNIP调节回路进一步协调细胞生长，因为mTORC1复合物负调控该回路。mTORC1阻断MondoA:Mlx转录活性，可能有助于mTORC1在驱动葡萄糖摄取和糖酵解中的良好功能。MondoA-TXNIP调控回路的重要性被其在乳腺癌、卵巢癌和潜在的其他癌症中可能的肿瘤抑制功能所强调。在这个应用中，我们建议研究MondoA:Mlx复合体如何感知和响应TCA循环中间体a-酮戊二酸。我们还将确定线粒体状态下游激活的转录网络以及这些网络对MondoA的依赖性。接下来，我们将确定MondoA:Mlx复合物的转录功能是如何由mTORC1复合物控制的，以及这种调控的广度。最后，我们将通过小鼠模型研究MondoA- TXNIP回路在乳腺癌中作为生长/肿瘤抑制因子的作用。这些研究将有助于更深入地了解生长因子信号通路、线粒体状态和营养有效性如何通过MondoA:Mlx复合体整合。鉴于这些通路的解除管制在人类恶性肿瘤中几乎是普遍存在的，我们希望这项工作将为癌症的治疗干预提供新的途径。