title: Protein-arginine methyltransferase 1 suppresses megakaryocytic differentiation via modulation of the p38 MAPK pathway in K562 cells.
abstract: Protein-arginine methyltransferase 1 (PRMT1) plays pivotal roles in various cellular processes. However, its role in megakaryocytic differentiation has yet to be investigated. Human leukemia K562 cells have been used as a model to study hematopoietic differentiation. In this study, we report that ectopic expression of HA-PRMT1 in K562 cells suppressed phorbol 12-myristate 13-acetate (PMA)-induced megakaryocytic differentiation as demonstrated by changes in cytological characteristics, adhesive properties, and CD41 expression, whereas knockdown of PRMT1 by small interference RNA promoted differentiation. Impairment of the methyltransferase activity of PRMT1 diminished the suppressive effect. These results provide evidence for a novel role of PRMT1 in negative regulation of megakaryocytic differentiation. Activation of ERK MAPK has been shown to be essential for megakaryocytic differentiation, although the role of p38 MAPK is still poorly understood. We show that knockdown of p38alpha MAPK or treatment with the p38 inhibitor SB203580 significantly enhanced PMA-induced megakaryocytic differentiation. Further investigation revealed that PRMT1 promotes activation of p38 MAPK without inhibiting activation of ERK MAPK. In p38alpha knockdown cells, PRMT1 could no longer suppress differentiation. In contrast, enforced expression of p38alpha MAPK suppressed PMA-induced megakaryocytic differentiation of parental K562 as well as PRMT1-knockdown cells. We propose modulation of the p38 MAPK pathway by PRMT1 as a novel mechanism regulating megakaryocytic differentiation. This study thus provides a new perspective on the promotion of megakaryopoiesis.
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Yuan-I
authors.initials: YI
authors.lastname: Chang
authors.forename: Wei-Kai
authors.initials: WK
authors.lastname: Hua
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yao
authors.forename: Shiaw-Min
authors.initials: SM
authors.lastname: Hwang
authors.forename: Yi-Chi
authors.initials: YC
authors.lastname: Hung
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Kuan
authors.forename: Jiun-Shyang
authors.initials: JS
authors.lastname: Leou
authors.forename: Wey-Jinq
authors.initials: WJ
authors.lastname: Lin
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D020014:K562 Cells / Q000166:cytology / Q000187:drug effects; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D011494:Protein Kinases / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D011494:Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D012259:Ribonuclease, Pancreatic; D013755:Tetradecanoylphorbol Acetate