title: Induction of megakaryocyte differentiation drives nuclear accumulation and transcriptional function of MKL1 via actin polymerization and RhoA activation.
abstract: How components of the cytoskeleton regulate complex cellular responses is fundamental to understanding cellular function. Megakaryoblast leukemia 1 (MKL1), an activator of serum response factor (SRF) transcriptional activity, promotes muscle, neuron, and megakaryocyte differentiation. In muscle cells, where MKL1 subcellular localization is one mechanism by which cells control SRF activity, MKL1 translocation from the cytoplasm to the nucleus in response to actin polymerization is critical for its function as a transcriptional regulator. MKL1 localization is cell-type specific; it is predominantly cytoplasmic in unstimulated fibroblasts and some muscle cell types and is constitutively nuclear in neuronal cells. In the present study, we report that in megakaryocytes, subcellular localization and regulation of MKL1 is dependent on RhoA activity and actin organization. Induction of megakaryocytic differentiation of human erythroleukemia cells by 12-O-tetradecanoylphorbol-13-acetate and primary megakaryocytes by thrombopoietin promotes MKL1 nuclear localization. This MKL1 localization is blocked by drugs inhibiting RhoA activity or actin polymerization.We also show that nuclear-localized MKL1 activates the transcription of SRF target genes. This report broadens our knowledge of the molecular mechanisms regulating megakaryocyte differentiation.
authors.affiliation: Departments of Cell Biology, Yale University School of Medicine, New Haven, CT 06520-8073, USA.
authors.forename: Elenoe C
authors.initials: EC
authors.lastname: Smith
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Teixeira
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Hahn
authors.forename: Diane S
authors.initials: DS
authors.lastname: Krause
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D055503:Protein Multimerization; D026362:Serum Response Factor / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013926:Thrombopoietin / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; D004268:DNA-Binding Proteins; C431575:MRTFA protein, human; D015514:Oncogene Proteins, Fusion; C476858:SRF protein, human; D026362:Serum Response Factor; D015534:Trans-Activators; C066737:RHOA protein, human; D013926:Thrombopoietin; D020742:rhoA GTP-Binding Protein; D013755:Tetradecanoylphorbol Acetate