The Role of the Fructose-1,6-Bisphoshatase 2 and c-Myc Interaction in Sarcoma Progression

果糖-1,6-双磷酸酶 2 和 c-Myc 相互作用在肉瘤进展中的作用

• 批准号: 10536204
• 负责人: Bailey Nance
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536204
• 关键词: Adult; Affect; Alanine; Alleles; Attenuated; Binding; Binding Sites; Biogenesis; Biological Assay; CDK4 gene; Cartilage; Cell Cycle; Cell Cycle Regulation; Cell Fractionation; Cell Nucleus; Cells; Co-Immunoprecipitations; Complement; Complex; Connective Tissue; Cytoplasm; Data; Dependence; Disease; Down-Regulation; Enzymes; Excision; Exhibits; Exposure to; Fatty acid glycerol esters; Fructose; Fructose-1,6-Bisphosphatase; Gene Expression; Genetic; Genetic Transcription; Gluconeogenesis; Glucose; Growth; Heterogeneity; Histologic; Hypoxia; In Vitro; Malignant Neoplasms; Maps; Measures; Mediating; Mesenchymal Cell Neoplasm; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Molecular Conformation; Mus; Muscle; N-terminal; Nuclear; Nuclear Export; Nuclear Translocation; Operative Surgical Procedures; Oxidative Phosphorylation; Patients; Play; Protein Isoforms; Proteins; Recurrence; Research; Resistance; Role; Scanning; Signal Transduction; Site; Site-Directed Mutagenesis; Soft tissue sarcoma; Stimulus; Structure; Therapeutic; analytical ultracentrifugation; aurora kinase A; c-myc Genes; cdc Genes; chemotherapy; combat; confocal imaging; conventional therapy; dimer; effective therapy; epigenetic silencing; experimental study; functional outcomes; genetic signature; glucose metabolism; glucose uptake; improved; in vivo; inhibitor; insight; mouse model; mutant; novel; novel therapeutics; prediction algorithm; promoter; protein protein interaction; restoration; sarcoma; sedimentation velocity; small molecule inhibitor; transcriptome sequencing; treatment response; tumor; tumor growth

PROJECT SUMMARY Soft tissue sarcomas (STSs) are diverse mesenchymal tumors that occur within connective tissues such as muscle, fat, and cartilage. STS is a highly heterogeneous malignancy with over 70 genetic and histological subtypes. In addition, high rates of recurrence and lack of effective treatment for patients emphasize the need to identify novel therapeutic vulnerabilities common to multiple STS subtypes. Metabolically, STS tumors consistently exhibit high rates of glucose uptake and robust hypoxia gene signatures in patients. Therefore, we focused on fructose-1,6-bisphosphatase (FBP), a rate-limiting enzyme in gluconeogenesis, to combat the typical glycolytic dependence of STS. In previous studies, we showed that FBP2, the muscle-specific isoform of FBP, is severely downregulated in several prevalent STS subtypes. Surprisingly, FBP2 re-expression in STS in vivo opposes sarcoma progression through two spatially distinct mechanisms in the cytoplasm and the nucleus. FBP2 restoration decreases cytosolic glycolytic flux while nuclear FBP2 directly binds to c-Myc, a transcriptional regulator of growth and metabolism. This interaction attenuates c-Myc-dependent expression of TFAM, a key regulator of mitochondrial biogenesis, thereby inhibiting oxidative phosphorylation. These mechanisms, at least in part, contribute to the ability of re-expressed FBP2 to suppress tumor growth in murine STS models. However, my preliminary data suggest that nuclear FBP2 may also directly regulate other c-Myc cell cycle target genes CDK4 and AURKA to contribute to STS suppression. Moreover, how FBP2 regulates c-Myc and the sites of FBP2/c-Myc binding are not known. Recent studies suggest that FBP2 oligomerization and conformation may also play an important role in FBP2's nuclear-to-cytosolic shuttling, and reveal new binding sites for other proteins in the nucleus like c-Myc. Therefore, I hypothesize that the exposed N-terminal regions of tetrameric FBP2 complexes bind directly to c-Myc, contributing to STS suppression by inhibiting both TFAM and cell cycle regulators. In Aim 1, I will map the sites of interaction between FBP2 and c-Myc and determine whether the tetrameric state of FBP2 is necessary for binding. In Aim 2, I will explore the functional outcomes of the FBP2/c-Myc interaction in sarcoma, including the regulation of cell cycle genes AURKA and CDK4. Together, this proposal will provide more insight into the recently discovered nuclear functions of FBP2 to create novel therapies for a diverse set of genetically heterogeneous sarcomas.

项目总结