VEGF regulation by the TSC2 tumor suppressor

TSC2 肿瘤抑制因子对 VEGF 的调节

• 批准号: 7421034
• 负责人: James Brugarolas
• 金额: $ 17.3万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-18 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7421034
• 关键词: Affect; Astrocytoma; Benign; Cells; Condition; Development; Disease; Down-Regulation; Enzymes; Exposure to; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Glucose; Growth; Growth Factor; Hypoxia; Hypoxia Inducible Factor; Link; Malignant Neoplasms; Maps; Metabolic; Mutation; Nutrient; Oxygen; Oxygen measurement, partial pressure, arterial; Pathway interactions; Phosphorylation; Protein-Serine-Threonine Kinases; Proteins; Regulation; Renal Cell Carcinoma; Signal Transduction; Sirolimus; Site; Structure; Suppressor Mutations; Syndrome; Thinking; Tissues; Translations; Tuberous sclerosis protein complex; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; VHL protein; Vascular Endothelial Growth Factors; Von Hippel-Lindau Syndrome; cell type; extracellular; gene function; human TSC2 protein; insight; loss of function mutation; mutant; programs; reconstitution; research study; response; transcription factor; tumor

DESCRIPTION (provided by applicant): Loss of function mutations in the Tuberous Sclerosis Complex 2 gene (TSC2) result in Tuberous Sclerosis Complex (TSC), a disease characterized by the development of tumors in many tissues.TSC2 is in a pathway that integrates extracellular signals from growth factors and nutrients with the protein translation apparatus but the contribution of this pathway to its tumor suppression function is unclear. Similarities between the cancer prone syndromes TSC and von Hippel-Lindau (resulting from mutations in the VHL tumor suppressor gene), led me to hypothesize the existence of a functional link between TSC2 and pVHL. I have now demonstrated that loss of TSC2, like loss of pVHL, results in the activation of a program of gene expression conferring a selective growth advantage to cells that is regulated by the transcription factor Hypoxia-lnducible Factor (HIF) (Brugarolas et al., 2003). TSC2 inactivation is sufficient to upregulate HIF and reconstitution of TSC2-deficient cells with a TSC2 disease-associated mutant, unlike with wild-type TSC2, fails to restore HIF regulation suggesting that this function is important for tumor suppression. Because HIF levels are normally regulated by changes in oxygen tension and this response is impaired in TSC2-deficient cells, I hypothesized that TSC2 function might also be regulated by changes in oxygen levels. Indeed, while wild-type cells downregulate mammalian Target of Rapamycin (mTOR) function in response to hypoxia, TSC2 deficient cells fail to do so, suggesting that TSC2 is required for mTOR inhibition under these conditions. Furthermore, exposure to hypoxia results in the rapid phosphorylation of TSC2. The experiments outlined in this proposal aim to unravel the mechanism whereby TSC2 function is regulated by hypoxia. A greater understanding of TSC2 regulation by hypoxia might provide insight into its function as a tumor suppressor.

描述（由申请人提供）： TSC 2基因的功能缺失突变导致了TSC 2在多种组织中发生肿瘤，TSC 2是一条整合来自生长因子和营养物质的细胞外信号与蛋白质翻译装置的途径，但该途径在其肿瘤抑制功能中的作用尚不清楚。癌症易感综合征TSC和von Hippel-Lindau（由VHL肿瘤抑制基因突变引起）之间的相似性使我假设TSC 2和pVHL之间存在功能联系。我现在已经证明，TSC 2的缺失，像pVHL的缺失一样，导致基因表达程序的激活，该基因表达程序赋予细胞选择性生长优势，该细胞由转录因子缺氧诱导因子（HIF）调节（Brugarolas等人，2003年）。TSC 2失活足以上调HIF，并且与野生型TSC 2不同，用TSC 2疾病相关突变体重建TSC 2缺陷细胞不能恢复HIF调节，这表明该功能对于肿瘤抑制很重要。由于HIF水平通常受氧张力变化的调节，而这种反应在TSC 2缺陷细胞中受损，因此我假设TSC 2功能也可能受氧水平变化的调节。事实上，虽然野生型细胞下调哺乳动物雷帕霉素靶蛋白（mTOR）功能以响应缺氧，但TSC 2缺陷型细胞不能做到这一点，表明TSC 2是在这些条件下抑制mTOR所必需的。此外，暴露于缺氧会导致TSC 2快速磷酸化。本提案中概述的实验旨在阐明TSC 2功能受缺氧调节的机制。更好地了解TSC 2通过缺氧调节可能会深入了解其作为肿瘤抑制因子的功能。