PROJ 11: RB PROTEIN INACTIVATION RESULTS IN A METABOLIC SHIFT TOWARDS GLUTAMINE

项目 11：RB 蛋白失活导致向谷氨酰胺的代谢转变

• 批准号: 8360673
• 负责人: Brian F Clem
• 金额: $ 23.96万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360673
• 关键词: Amino Acids; Biochemical Pathway; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cell Survival; Cells; Centers of Research Excellence; Consumption; Data; Dependence; Embryo; Enzymes; Fibroblasts; Funding; Genes; Glucose; Glutamine; Glutathione; Grant; Knockout Mice; Mediating; Metabolic; Metabolism; Molecular Target; National Center for Research Resources; Nature; Nucleotides; Oncogenic; Pathway interactions; Phenotype; Play; Principal Investigator; Production; Proteins; Regulation; Research; Research Infrastructure; Resources; Retinoblastoma Protein; Role; Signal Transduction; Source; Transcript; Tumor Suppressor Proteins; United States National Institutes of Health; Work; addiction; c-myc Genes; cell growth; cost; neoplastic; neoplastic cell; tumorigenesis; tumorigenic

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Retinoblastoma protein (Rb), the first described tumor suppressor, plays a vital role in regulating cell proliferation by modulating the expression of key genes involved in cell cycle progression. Although the majority of work investigating the role of Rb function in tumorigenesis has focused on cell cycle regulation, it is clear that Rb may mediate a broad spectrum of biochemical pathways, particularly those involved in cellular metabolism. Dysregulated metabolism is now considered a hallmark of tumorigenic cells, as evident by increased glucose utilization as well as a dependence on glutamine consumption. Specifically, glutamine serves to fulfill the metabolic need for energy production, nucleotide and amino acid synthesis, and the production of glutathione. Even though specific enzymes have been implicated in this phenomenon of "glutamine addiction" in tumor cells, the precise signaling mechanisms and the oncogenic factors that facilitate this metabolic shift have yet to be fully described. Using genetically depleted Rb knockout mouse embryonic fibroblasts, we demonstrate that Rb inactivation specifically leads to a dependence on glutamine for cell growth and survival. Our data further suggest that this metabolic shift may be through a c-Myc dependent pathway, as Rb depletion increases both c-Myc transcript and protein levels. At the completion of this proposal, we expect to have fully characterized the regulation of glutamine metabolism by Rb, and in doing so provide a greater understanding of the nature of the neoplastic phenotype, especially with respect to disruption of the Rb network.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 视网膜母细胞瘤蛋白（Retinoblastoma protein，Rb）是第一个被发现的肿瘤抑制因子，通过调控细胞周期进程中的关键基因的表达，在细胞增殖调控中起重要作用。虽然大多数研究Rb功能在肿瘤发生中的作用的工作都集中在细胞周期调控上，但很明显Rb可能介导广泛的生化途径，特别是那些参与细胞代谢的途径。代谢失调现在被认为是致瘤细胞的标志，如葡萄糖利用增加以及对谷氨酰胺消耗的依赖所证明的。具体而言，谷氨酰胺用于满足能量产生、核苷酸和氨基酸合成以及谷胱甘肽产生的代谢需要。尽管特定的酶与肿瘤细胞中的“谷氨酰胺成瘾”现象有关，但促进这种代谢转变的精确信号传导机制和致癌因子尚未得到充分描述。使用基因耗尽的Rb基因敲除小鼠胚胎成纤维细胞，我们表明，Rb失活具体导致依赖谷氨酰胺的细胞生长和生存。我们的数据进一步表明，这种代谢转变可能是通过c-Myc依赖性途径，Rb耗竭增加c-Myc转录和蛋白水平。在完成这一建议，我们希望有充分的特点，由Rb谷氨酰胺代谢的调节，并在这样做提供了一个更好的理解的性质的肿瘤表型，特别是关于Rb网络的中断。