Τίτλος:
RASSF1A is required for the maintenance of nuclear actin levels
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Nuclear actin participates in many essential cellular processes including gene transcription, chromatin remodelling and mRNA processing. Actin shuttles into and out the nucleus through the action of dedicated transport receptors importin-9 and exportin-6, but how this transport is regulated remains unclear. Here, we show that RASSF1A is a novel regulator of actin nucleocytoplasmic trafficking and is required for the active maintenance of nuclear actin levels through supporting binding of exportin-6 (XPO6) to RAN GTPase. RASSF1A (Ras association domain family 1 isoform A) is a tumour suppressor gene frequently silenced by promoter hypermethylation in all major solid cancers. Specifically, we demonstrate that endogenous RASSF1A localises to the nuclear envelope (NE) and is required for nucleocytoplasmic actin transport and the concomitant regulation of myocardin-related transcription factor A (MRTF-A), a co-activator of the transcription factor serum response factor (SRF). The RASSF1A/RAN/XPO6/nuclear actin pathway is aberrant in cancer cells where RASSF1A expression is lost and correlates with reduced MRTF-A/SRF activity leading to cell adhesion defects. Taken together, we have identified a previously unknown mechanism by which the nuclear actin pool is regulated and uncovered a previously unknown link of RASSF1A and MRTF-A/SRF in tumour suppression. © 2019 The Authors. Published under the terms of the CC BY 4.0 license
Συγγραφείς:
Chatzifrangkeskou, M.
Pefani, D.-E.
Eyres, M.
Vendrell, I.
Fischer, R.
Pankova, D.
O'Neill, E.
Εκδότης:
Wiley-VCH Verlag
Λέξεις-κλειδιά:
actin; exportin 6; guanosine triphosphatase; messenger RNA; myocardin; myocardin related transcription factor A; nuclear protein; Ras association domain family protein 1A; serum response factor; unclassified drug; actin; exportin 6 protein, human; karyopherin; MRTFA protein, human; RASSF1 protein, human; serum response factor; SRF protein, human; transactivator protein; tumor suppressor protein, Article; breast cancer; cancer prognosis; controlled study; DNA methylation; gene silencing; liver cancer; priority journal; protein domain; protein expression; protein function; protein localization; protein protein interaction; RASSF1A gene; breast tumor; cell nucleus membrane; cytoplasm; down regulation; female; gene expression regulation; genetics; HEK293 cell line; HeLa cell line; human; liver tumor; metabolism; prognosis; transport at the cellular level; tumor cell line, Actins; Biological Transport; Breast Neoplasms; Cell Line, Tumor; Cytoplasm; DNA Methylation; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; HeLa Cells; Humans; Karyopherins; Liver Neoplasms; Nuclear Envelope; Prognosis; Serum Response Factor; Trans-Activators; Tumor Suppressor Proteins
DOI:
10.15252/embj.2018101168
