Browsing by Author "Chen, Yabing"

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    Methylation of dual-specificity phosphatase 4 controls cell differentiation
    (Cell Press, 2021) Su, Hairui; Jiang, Ming; Senevirathne, Chamara; Aluri, Srinivas; Zhang, Tuo; Guo, Han; Xavier-Ferrucio, Juliana; Jin, Shuiling; Tran, Ngoc-Tung; Liu, Szu-Mam; Sun, Chiao-Wang; Zhu, Yongxia; Zhao, Qing; Chen, Yuling; Cable, LouAnn; Shen, Yudao; Liu, Jing; Qu, Cheng-Kui; Han, Xiaosi; Klug, Christopher A.; Bhatia, Ravi; Chen, Yabing; Nimer, Stephen D.; Zheng, Y. George; Iancu-Rubin, Camelia; Jin, Jian; Deng, Haiteng; Krause, Diane S.; Xiang, Jenny; Verma, Amit; Luo, Minkui; Zhao, Xinyang; Pediatrics, School of Medicine
    Mitogen-activated protein kinases (MAPKs) are inactivated by dual-specificity phosphatases (DUSPs), the activities of which are tightly regulated during cell differentiation. Using knockdown screening and single-cell transcriptional analysis, we demonstrate that DUSP4 is the phosphatase that specifically inactivates p38 kinase to promote megakaryocyte (Mk) differentiation. Mechanistically, PRMT1-mediated methylation of DUSP4 triggers its ubiquitinylation by an E3 ligase HUWE1. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation in Mk cells. In the context of thrombocytopenia observed in myelodysplastic syndrome (MDS), we demonstrate that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis. These findings provide mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a strategy for treatment of thrombocytopenia associated with MDS.
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    Phosphate in Cardiovascular Disease: From New Insights Into Molecular Mechanisms to Clinical Implications
    (American Heart Association, 2024) Turner, Mandy E.; Beck, Laurent; Hill Gallant, Kathleen M.; Chen, Yabing; Moe, Orson W.; Kuro-o, Makoto; Moe, Sharon; Aikawa, Elena; Medicine, School of Medicine
    Hyperphosphatemia is a common feature in patients with impaired kidney function and is associated with increased risk of cardiovascular disease. This phenomenon extends to the general population, whereby elevations of serum phosphate within the normal range increase risk; however, the mechanism by which this occurs is multifaceted, and many aspects are poorly understood. Less than 1% of total body phosphate is found in the circulation and extracellular space, and its regulation involves multiple organ cross talk and hormones to coordinate absorption from the small intestine and excretion by the kidneys. For phosphate to be regulated, it must be sensed. While mostly enigmatic, various phosphate sensors have been elucidated in recent years. Phosphate in the circulation can be buffered, either through regulated exchange between extracellular and cellular spaces or through chelation by circulating proteins (ie, fetuin-A) to form calciprotein particles, which in themselves serve a function for bulk mineral transport and signaling. Either through direct signaling or through mediators like hormones, calciprotein particles, or calcifying extracellular vesicles, phosphate can induce various cardiovascular disease pathologies: most notably, ectopic cardiovascular calcification but also left ventricular hypertrophy, as well as bone and kidney diseases, which then propagate phosphate dysregulation further. Therapies targeting phosphate have mostly focused on intestinal binding, of which appreciation and understanding of paracellular transport has greatly advanced the field. However, pharmacotherapies that target cardiovascular consequences of phosphate directly, such as vascular calcification, are still an area of great unmet medical need.