The role of phosphorylation of isocitrate dehydrogenase in breast cancer

异柠檬酸脱氢酶磷酸化在乳腺癌中的作用

• 批准号: 10090749
• 负责人: Chenguang Fan
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10090749
• 关键词: Address; Arkansas; Bacteria; Bioenergetics; Breast Cancer Cell; Breast Cancer Patient; Breast Epithelial Cells; Cancerous; Cell Proliferation; Cells; Citrate (si)-Synthase; Citric Acid Cycle; Crystallization; Data; Data Analyses; Data Science; Data Science Core; Detection; Development; Diagnosis; Disease; Enzymes; Generations; Genetic Code; Glutamates; Goals; Heterogeneity; Homeostasis; Homologous Gene; Human; Human Cell Line; Image; Individual; Investigation; Isocitrate Dehydrogenase; Kinetics; Knowledge; Link; Malate Dehydrogenase; Malignant Neoplasms; Measures; Mentors; Metabolic; Metabolism; Methods; Molecular; Mutation; Oncogenic; Oxidation-Reduction; Pathway Analysis; Pathway interactions; Phosphoamino Acids; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Production; Protein Isoforms; Protein Kinase; Proteins; Recombinants; Reporting; Research; Role; Signal Pathway; Site; Somatic Mutation; Structural Models; Structure; Substrate Specificity; System; Techniques; Testing; Tissues; Variant; Woman; Women' s Health; Work; base; breast cancer diagnosis; cancer cell; cancer therapy; cofactor; experimental study; innovation; malignant breast neoplasm; metabolic imaging; novel marker; phosphoproteomics; repaired; spectroscopic imaging; therapeutic target

Project Summary – Project Leader Chenguang Fan Breast cancer is one of the top threats to women’s health. About 1 in 8 US women (~12%) will develop invasive breast cancer over the course of her lifetime. Previous studies have shown the important role of a key tricarboxylic acid cycle (TCA) enzyme isocitrate dehydrogenase (IDH) in breast cancer. A variety of IDH alternations including somatic mutations, aberrant expression, and altered activities have been observed in breast cancer patients. Recently, phosphoproteomic studies of breast cancer cells have identified several unique phosphorylation sites in IDH isoforms, and those sites are specific for different types of breast cancer. Such heterogeneity poses challenges for effective diagnosis and treatment, so there is a critical need to discover specific mechanisms of IDH phosphorylation for breast cancer. The overall goal of this project is to identify the role of IDH phosphorylation in breast cancer. As IDH homologues in bacteria are known to be regulated by phosphorylation, the hypothesis is that phosphorylation of IDH in human cells alters IDH functions and cellular metabolism, thus facilitating cancerous transformations. To test this hypothesis, three specific aims are proposed: Aim 1 is to identify the effects of phosphorylation on IDH enzyme functions at the molecular level. Aim 2 is to identify the influences of IDH phosphorylation on cellular metabolism and redox status at the metabolic level. Aim 3 is to identify mechanisms or pathways in which IDH phosphorylation plays roles in breast cancer at the cellular level. The oncogenic transformation test on normal human mammary epithelial cells will be performed to identify whether IDH phosphorylation is an initiator for breast cancer or a cellular adaption to facilitate cancer formation. This proposal is innovative because: 1) the functions of IDH phosphorylation in human remain largely unknown, and this proposal will be the first to systematically study the phosphorylation of all the three IDH isoforms in human cells; 2) To address the problem that the classic glutamate-substitution method for phosphorylation studies is not always effective, the genetic code expansion technique will be applied in this proposal to co-translationally incorporate phosphoamino acid (pAA) at a controlled site in target proteins in order to produce site-specifically phosphorylated IDH variants which have been identified in breast cancer. This proposal will be the first to introduce pAA-incorporation systems into human cell lines to study phosphorylation in living cells. The proposed research is significant because it will provide key evidence for the influences and roles of IDH phosphorylation in breast cancer. Given that protein phosphorylation is usually involved in signaling pathways through different kinase cascades, the role of IDH phosphorylation in breast cancer could be different from other IDH alternations. Ultimately, the proposed studies on IDH phosphorylation are expected to identify novel biomarker and targets for breast cancer diagnosis and treatment.

项目总结-项目负责人范晨光