6 results on '"Hyuk-Soo Seo"'
Search Results
2. Structural and functional consequences of the STAT5BN642H driver mutation
- Author
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Elvin D. de Araujo, Fettah Erdogan, Heidi A. Neubauer, Deniz Meneksedag-Erol, Pimyupa Manaswiyoungkul, Mohammad S. Eram, Hyuk-Soo Seo, Abdul K. Qadree, Johan Israelian, Anna Orlova, Tobias Suske, Ha T. T. Pham, Auke Boersma, Simone Tangermann, Lukas Kenner, Thomas Rülicke, Aiping Dong, Manimekalai Ravichandran, Peter J. Brown, Gerald F. Audette, Sarah Rauscher, Sirano Dhe-Paganon, Richard Moriggl, and Patrick T. Gunning
- Subjects
Science - Abstract
Hyper-activated STAT5B and its disease-causing variants are of interest as cancer drug targets. Here the authors combine cell based studies, X-ray crystallography, biophysical experiments and MD simulations to structurally and functionally characterize the STAT5BN642H mutant found in aggressive T-cell leukemia and lymphomas and find that it has an increased affinity for self-dimerization.
- Published
- 2019
- Full Text
- View/download PDF
3. Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells
- Author
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Shingo Kozono, Yu-Min Lin, Hyuk-Soo Seo, Benika Pinch, Xiaolan Lian, Chenxi Qiu, Megan K. Herbert, Chun-Hau Chen, Li Tan, Ziang Jeff Gao, Walter Massefski, Zainab M. Doctor, Brian P. Jackson, Yuanzhong Chen, Sirano Dhe-Paganon, Kun Ping Lu, and Xiao Zhen Zhou
- Subjects
Science - Abstract
Arsenic trioxide and all-trans retinoic acid combination safely cures human acute promyelocytic leukemia. Here, the authors show that this combination has potent anticancer activity in triple negative breast cancer by cooperatively targeting Pin1, a master regulator of oncogenic signaling networks, to eliminate cancer stem cells.
- Published
- 2018
- Full Text
- View/download PDF
4. Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency
- Author
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Michelle S, Prew, Christina M, Camara, Thomas, Botzanowski, Jamie A, Moroco, Noah B, Bloch, Hannah R, Levy, Hyuk-Soo, Seo, Sirano, Dhe-Paganon, Gregory H, Bird, Henry D, Herce, Micah A, Gygi, Silvia, Escudero, Thomas E, Wales, John R, Engen, and Loren D, Walensky
- Subjects
Mitochondrial Diseases ,Muscular Diseases ,Acyl-CoA Dehydrogenase, Long-Chain ,Congenital Bone Marrow Failure Syndromes ,Humans ,Lipid Metabolism, Inborn Errors - Abstract
Very long-chain acyl-CoA dehydrogenase (VLCAD) is an inner mitochondrial membrane enzyme that catalyzes the first and rate-limiting step of long-chain fatty acid oxidation. Point mutations in human VLCAD can produce an inborn error of metabolism called VLCAD deficiency that can lead to severe pathophysiologic consequences, including cardiomyopathy, hypoglycemia, and rhabdomyolysis. Discrete mutations in a structurally-uncharacterized C-terminal domain region of VLCAD cause enzymatic deficiency by an incompletely defined mechanism. Here, we conducted a structure-function study, incorporating X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, computational modeling, and biochemical analyses, to characterize a specific membrane interaction defect of full-length, human VLCAD bearing the clinically-observed mutations, A450P or L462P. By disrupting a predicted α-helical hairpin, these mutations either partially or completely impair direct interaction with the membrane itself. Thus, our data support a structural basis for VLCAD deficiency in patients with discrete mutations in an α-helical membrane-binding motif, resulting in pathologic enzyme mislocalization.
- Published
- 2021
5. Structural and functional consequences of the STAT5BN642H driver mutation
- Author
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Richard Moriggl, Manimekalai Ravichandran, Thomas Rülicke, Lukas Kenner, Peter Brown, Sarah Rauscher, Mohammad S. Eram, Ha T. T. Pham, Fettah Erdogan, Deniz Meneksedag-Erol, Simone Tangermann, Aiping Dong, Auke Boersma, Patrick T. Gunning, Pimyupa Manaswiyoungkul, Elvin D. de Araujo, Hyuk-Soo Seo, Sirano Dhe-Paganon, Abdul K. Qadree, Gerald F. Audette, Johan Israelian, Anna Orlova, Heidi A. Neubauer, and Tobias Suske
- Subjects
0301 basic medicine ,Genetically modified mouse ,Science ,Transgene ,Mutant ,General Physics and Astronomy ,STAT5B ,02 engineering and technology ,Biology ,SH2 domain ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,medicine ,lcsh:Science ,Multidisciplinary ,General Chemistry ,021001 nanoscience & nanotechnology ,medicine.disease ,3. Good health ,Lymphoma ,Haematopoiesis ,Leukemia ,030104 developmental biology ,Cancer research ,lcsh:Q ,0210 nano-technology - Abstract
Hyper-activated STAT5B variants are high value oncology targets for pharmacologic intervention. STAT5BN642H, a frequently-occurring oncogenic driver mutation, promotes aggressive T-cell leukemia/lymphoma in patient carriers, although the molecular origins remain unclear. Herein, we emphasize the aggressive nature of STAT5BN642H in driving T-cell neoplasia upon hematopoietic expression in transgenic mice, revealing evidence of multiple T-cell subset organ infiltration. Notably, we demonstrate STAT5BN642H-driven transformation of γδ T-cells in in vivo syngeneic transplant models, comparable to STAT5BN642H patient γδ T-cell entities. Importantly, we present human STAT5B and STAT5BN642H crystal structures, which propose alternative mutation-mediated SH2 domain conformations. Our biophysical data suggests STAT5BN642H can adopt a hyper-activated and hyper-inactivated state with resistance to dephosphorylation. MD simulations support sustained interchain cross-domain interactions in STAT5BN642H, conferring kinetic stability to the mutant anti-parallel dimer. This study provides a molecular explanation for the STAT5BN642H activating potential, and insights into pre-clinical models for targeted intervention of hyper-activated STAT5B.
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- 2019
6. Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells
- Author
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Megan K. Herbert, Zainab M. Doctor, Hyuk-Soo Seo, Sirano Dhe-Paganon, Kun Ping Lu, Li Tan, Xiao Zhen Zhou, Chenxi Qiu, Brian P. Jackson, Yuanzhong Chen, Yu-Min Lin, Walter Massefski, Chun-Hau Chen, Shingo Kozono, Ziang Jeff Gao, Benika J. Pinch, and Xiaolan Lian
- Subjects
Proteomics ,0301 basic medicine ,Acute promyelocytic leukemia ,Magnetic Resonance Spectroscopy ,Science ,Retinoic acid ,General Physics and Astronomy ,Antineoplastic Agents ,Tretinoin ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Arsenic Trioxide ,Leukemia, Promyelocytic, Acute ,Cancer stem cell ,Neoplasms ,medicine ,Animals ,Humans ,Arsenic trioxide ,lcsh:Science ,neoplasms ,Triple-negative breast cancer ,Cell Proliferation ,Mice, Knockout ,Mice, Inbred BALB C ,Multidisciplinary ,organic chemicals ,Gene Expression Profiling ,Cancer ,General Chemistry ,Fibroblasts ,medicine.disease ,biological factors ,3. Good health ,Gene Expression Regulation, Neoplastic ,NIMA-Interacting Peptidylprolyl Isomerase ,Leukemia ,030104 developmental biology ,chemistry ,Cancer research ,PIN1 ,Female ,lcsh:Q ,Neoplasm Transplantation ,Signal Transduction - Abstract
Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but their mechanisms of action and efficacy are not fully understood. ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1’s active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, like Pin1 knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic targeting of Pin1 by ATO and ATRA offers an attractive approach to combating breast and other cancers., Arsenic trioxide and all-trans retinoic acid combination safely cures human acute promyelocytic leukemia. Here, the authors show that this combination has potent anticancer activity in triple negative breast cancer by cooperatively targeting Pin1, a master regulator of oncogenic signaling networks, to eliminate cancer stem cells.
- Published
- 2018
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