7 results on '"Ming O. Li"'
Search Results
2. Cancer immunotherapy via targeted TGF-β signalling blockade in T
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Shun, Li, Ming, Liu, Mytrang H, Do, Chun, Chou, Efstathios G, Stamatiades, Briana G, Nixon, Wei, Shi, Xian, Zhang, Peng, Li, Shengyu, Gao, Kristelle J, Capistrano, Hong, Xu, Nai-Kong V, Cheung, and Ming O, Li
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Male ,Vascular Endothelial Growth Factor A ,Cell Death ,Receptor, Transforming Growth Factor-beta Type II ,Antibodies, Monoclonal ,Breast Neoplasms ,T-Lymphocytes, Helper-Inducer ,Cell Hypoxia ,Mice ,HEK293 Cells ,Transforming Growth Factor beta ,Cell Line, Tumor ,Animals ,Humans ,Female ,Immunotherapy ,Interleukin-4 ,Lymph Nodes ,Signal Transduction - Abstract
Cancer arises from malignant cells that exist in dynamic multilevel interactions with the host tissue. Cancer therapies aiming to directly kill cancer cells, including oncogene-targeted therapy and immune-checkpoint therapy that revives tumour-reactive cytotoxic T lymphocytes, are effective in some patients
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- 2019
3. Author Correction: Comprehensive molecular profiling of lung adenocarcinoma
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Ming O. Li
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0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Multidisciplinary ,030220 oncology & carcinogenesis ,Data mining ,computer.software_genre ,computer ,Article ,Mathematics - Abstract
Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.
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- 2018
4. Author Correction: SZT2 dictates GATOR control of mTORC1 signalling
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Min Peng, Ming O. Li, and Na Yin
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Blot ,Multidisciplinary ,Signalling ,Published Erratum ,Computational biology ,Biology ,Article - Abstract
Target of rapamycin complex 1 (TORC1) integrates nutrient signals to control cell growth and organismal homeostasis across eukaryotes1–4. The evolutionarily conserved GATOR complex regulates TORC1 signaling through Rag GTPases with GATOR1 displaying GTPase activating protein (GAP) activity towards RagA/B and GATOR2 proposed as an inhibitor of GATOR15,6. Furthermore, the metazoan-specific Sestrin proteins function as guanine nucleotide dissociation inhibitors (GDIs) for RagA/B, and interact with GATOR2 with unknown functions7–9. Here we show that SZT2, a metazoan-specific protein mutated in epilepsy10–13, recruits a fraction of mammalian GATOR1 and GATOR2 to form SZT2-Orchestrated GATOR (SOG) complex with an essential role in GATOR- and Sestrin-dependent nutrient sensing and mTORC1 regulation. SZT2 interaction with GATOR1 and GATOR2 was cooperative, and an integral SOG was required for its localization on the lysosome. SZT2 deficiency resulted in constitutive mTORC1 signaling in cells under nutrient deprivation conditions and neonatal lethality in mice associated with failed mTORC1 inactivation during fasting. mTORC1 hyperactivation in SZT2-deficient cells could be partially corrected by overexpression of the GATOR1 component DEPDC5, and by a lysosome-targeted GATOR2 component WDR59 or a lysosome-targeted Sestrin2. These findings demonstrate a central role of SZT2 in dictating GATOR-dependent nutrient sensing by promoting lysosomal localization of SOG, and reveal an unexpected function of lysosome-located GATOR2 in suppressing mTORC1 signaling via Sestrin recruitment.
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- 2018
5. Novel Foxo1-dependent transcriptional programs control T-reg cell function
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Keji Zhao, Yifan Mo, Alexander Y. Rudensky, Michael Q. Zhang, Ming O. Li, Pamela Chan, Dies Meijer, Will Liao, Gurinder S. Atwal, Chong T. Luo, Myoungjoo V. Kim, Morgan Huse, Weiming Ouyang, Na Yin, Qian Ma, Min Peng, and Molecular Genetics
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Male ,endocrine system ,Transcription, Genetic ,medicine.medical_treatment ,Receptors, Antigen, T-Cell ,FOXO1 ,chemical and pharmacologic phenomena ,Biology ,T-Lymphocytes, Regulatory ,Article ,Interferon-gamma ,Mice ,Immune system ,Immune Tolerance ,medicine ,Animals ,Protein kinase B ,Transcription factor ,Cell Nucleus ,Binding Sites ,Genome ,Multidisciplinary ,Forkhead Box Protein O1 ,Forkhead Box Protein O3 ,Lymphocyte differentiation ,FOXP3 ,Forkhead Transcription Factors ,hemic and immune systems ,Research Highlight ,Molecular biology ,Cell biology ,Mice, Inbred C57BL ,Cytokine ,Gene Expression Regulation ,Female ,Proto-Oncogene Proteins c-akt ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
Regulatory T (T-reg) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses(1-4). Foxp3 operates as a late-acting differentiation factor controlling T-reg cell homeostasis and function(5), whereas the early T-reg-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors(6-10). However, whether Foxo proteins act beyond the T-reg-cell-commitment stage to control T-reg cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of T-reg cell function. T-reg cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with T-reg-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of T-reg cells. Genome-wide analysis of Foxo1 binding sites reveals similar to 300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt-Foxo1 signalling module controls a novel genetic program indispensable for T-reg cell function.
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- 2012
6. SZT2 dictates GATOR control of mTORC1 signalling
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Min Peng, Ming O. Li, and Na Yin
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0301 basic medicine ,GTPase-activating protein ,Nerve Tissue Proteins ,Nutrient sensing ,mTORC1 ,GTPase ,Biology ,Mechanistic Target of Rapamycin Complex 1 ,Cell Line ,03 medical and health sciences ,Mice ,Lysosome ,medicine ,Animals ,Humans ,Monomeric GTP-Binding Proteins ,Multidisciplinary ,Guanine Nucleotide Dissociation Inhibitors ,TOR Serine-Threonine Kinases ,GTPase-Activating Proteins ,Nuclear Proteins ,Fasting ,Repressor Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Biochemistry ,Animals, Newborn ,Peroxidases ,Food ,Multiprotein Complexes ,Female ,Signal transduction ,Carrier Proteins ,Food Deprivation ,Lysosomes ,Function (biology) ,Signal Transduction - Abstract
Mechanistic target of rapamycin complex 1 (TORC1) integrates nutrient signals to control cell growth and organismal homeostasis across eukaryotes. The evolutionarily conserved GATOR complex regulates mTORC1 signalling through Rag GTPases, and GATOR1 displays GTPase activating protein (GAP) activity for RAGA and RAGB (RAGA/B) and GATOR2 has been proposed to be an inhibitor of GATOR1. Furthermore, the metazoan-specific SESN proteins function as guanine nucleotide dissociation inhibitors (GDIs) for RAGA/B, and interact with GATOR2 with unknown effects. Here we show that SZT2 (seizure threshold 2), a metazoan-specific protein mutated in epilepsy, recruits a fraction of mammalian GATOR1 and GATOR2 to form a SZT2-orchestrated GATOR (SOG) complex with an essential role in GATOR- and SESN-dependent nutrient sensing and mTORC1 regulation. The interaction of SZT2 with GATOR1 and GATOR2 was synergistic, and an intact SOG complex was required for its localization at the lysosome. SZT2 deficiency resulted in constitutive mTORC1 signalling in cells under nutrient-deprived conditions and neonatal lethality in mice, which was associated with failure to inactivate mTORC1 during fasting. Hyperactivation of mTORC1 in SZT2-deficient cells could be partially corrected by overexpression of the GATOR1 component DEPDC5, and by the lysosome-targeted GATOR2 component WDR59 or lysosome-targeted SESN2. These findings demonstrate that SZT2 has a central role in dictating GATOR-dependent nutrient sensing by promoting lysosomal localization of SOG, and reveal an unexpected function of lysosome-located GATOR2 in suppressing mTORC1 signalling through SESN recruitment.
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- 2015
7. Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity
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Ahmed Toure, Will Liao, Ming O. Li, Saïda Dadi, and Chong T. Luo
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0301 basic medicine ,Male ,Transcription, Genetic ,Cellular differentiation ,Down-Regulation ,chemical and pharmacologic phenomena ,Autoimmunity ,Biology ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Article ,Immune tolerance ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Downregulation and upregulation ,Cell Movement ,Neoplasms ,medicine ,Immune Tolerance ,Animals ,Phosphorylation ,Multidisciplinary ,Forkhead Box Protein O1 ,FOXP3 ,hemic and immune systems ,Cell Differentiation ,Forkhead Transcription Factors ,Cell biology ,030104 developmental biology ,Immunology ,Mutation ,Female ,CD8 ,030215 immunology ,Homing (hematopoietic) ,Signal Transduction - Abstract
Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance1-5; yet, excessive Treg cell activities suppress anti-tumor immune responses6-8. Compared to resting phenotype Treg (rTreg) cells in the secondary lymphoid organs, Treg cells in non-lymphoid tissues including solid tumors exhibit an activated Treg (aTreg) cell phenotype9-11. However, aTreg cell function and whether its generation can be manipulated to promote tumor immunity without evoking autoimmunity are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases12,13, has an unexpected function in inhibiting aTreg cell-mediated immune tolerance. We found that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. Transcriptome analysis revealed that aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression and enhanced Foxo1 phosphorylation at sites of the Akt kinase. Treg cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and depleted aTreg cells, causing CD8+ T cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumor-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumor-associated Treg cells, activate effector CD8+ T cells, and inhibit tumor growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the generation of aTreg cells that have a crucial function in suppressing CD8+ T cell responses; and the Foxo signaling pathway in Treg cells can be titrated to preferentially break tumor immune tolerance.
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- 2015
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