Nuclear actin regulates cell proliferation and migration via inhibition of SRF and TEAD.

Autor: McNeill MC; School of Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK., Wray J; School of Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK., Sala-Newby GB; School of Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK., Hindmarch CCT; Queen's Cardiopulmonary Unit (QCPU), Translational Institute of Medicine (TIME), Department of Medicine, Queen's University, Kingston, ON K7L3N6, Canada., Smith SA; School of Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK., Ebrahimighaei R; School of Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK., Newby AC; School of Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK., Bond M; School of Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK. Electronic address: mark.bond@bris.ac.uk.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular cell research [Biochim Biophys Acta Mol Cell Res] 2020 Jul; Vol. 1867 (7), pp. 118691. Date of Electronic Publication: 2020 Feb 28.
DOI: 10.1016/j.bbamcr.2020.118691
Abstrakt: Actin dynamics regulate cell behaviour in response to physiological signals. Here we demonstrate a novel role for nuclear actin in inhibiting cell proliferation and migration. We demonstrate that physiological signals that elevate cAMP, which is anti-mitogenic in vascular smooth muscle cells, increases nuclear actin monomer levels. Expression of a nuclear-targeted polymerisation-defective actin mutant (NLS-Actin R62D ) inhibited proliferation and migration. Preventing nuclear actin monomer accumulation by enhancing its nuclear export or polymerisation reversed the anti-mitogenic and anti-migratory effects of cAMP. Transcriptomic analysis identified repression of proliferation and migration associated genes regulated by serum response factor (SRF) and TEA Domain (TEAD) transcription factors. Accordingly, NLS-Actin R62D inhibited SRF and TEAD activity and target gene expression, and these effects were reversed by constitutively-active mutants of the TEAD and SRF co-factors YAP, TAZ and MKL1. In summary, intranuclear actin inhibits proliferation and migration by inhibiting YAP-TEAD and MKL-SRF activity. This mechanism explains the anti-mitogenic and anti-migratory properties of physiological signals that elevate cAMP. SUMMARY: McNeill et al show that increased levels of intranuclear actin monomer inhibit cell proliferation and migration by inhibiting MKL1-SRF and YAP/TAZ-TEAD-dependent gene expression. This mechanism mediates the anti-mitogenic and anti-migratory effects of physiological signals that elevate cyclic-AMP.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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