Destabilization of nucleophosmin mRNA by the HuR/KSRP complex is required for muscle fibre formation

Anne Cammas, Brenda Janice Sanchez, Xian Jin Lian, Virginie Dormoy-Raclet, Kate van der Giessen, Isabel López de Silanes, Jennifer Ma, Carol Wilusz, John Richardson, Myriam Gorospe, Stefania Millevoi, Matteo Giovarelli, Roberto Gherzi, Sergio Di Marco and Imed-Eddine Gallouzi ()
Additional contact information
Anne Cammas: Goodman Cancer Center, McGill University
Brenda Janice Sanchez: Goodman Cancer Center, McGill University
Xian Jin Lian: Goodman Cancer Center, McGill University
Virginie Dormoy-Raclet: Goodman Cancer Center, McGill University
Kate van der Giessen: Goodman Cancer Center, McGill University
Isabel López de Silanes: Spanish National Cancer Research Centre (CNIO) Telomeres and Telomerase Group, Molecular Oncology Program
Jennifer Ma: Goodman Cancer Center, McGill University
Carol Wilusz: Immunology, and Pathology, Colorado State University
John Richardson: McGill University
Myriam Gorospe: National Institute on Aging, National Institutes of Health, Biomedical Research Center
Stefania Millevoi: INSERM, UMR 1037, Centre de Recherche en Cancérologie de Toulouse
Matteo Giovarelli: Istituto Nazionale Ricerca sul Cancro (IST), Laboratory of Gene Expression Regulation
Roberto Gherzi: Istituto Nazionale Ricerca sul Cancro (IST), Laboratory of Gene Expression Regulation
Sergio Di Marco: Goodman Cancer Center, McGill University
Imed-Eddine Gallouzi: Goodman Cancer Center, McGill University

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: Abstract HuR promotes myogenesis by stabilizing the MyoD, myogenin and p21 mRNAs during the fusion of muscle cells to form myotubes. Here we show that HuR, via a novel mRNA destabilizing activity, promotes the early steps of myogenesis by reducing the expression of the cell cycle promoter nucleophosmin (NPM). Depletion of HuR stabilizes the NPM mRNA, increases NPM protein levels and inhibits myogenesis, while its overexpression elicits the opposite effects. NPM mRNA destabilization involves the association of HuR with the decay factor KSRP as well as the ribonuclease PARN and the exosome. The C terminus of HuR mediates the formation of the HuR–KSRP complex and is sufficient for maintaining a low level of the NPM mRNA as well as promoting the commitment of muscle cells to myogenesis. We therefore propose a model whereby the downregulation of the NPM mRNA, mediated by HuR, KSRP and its associated ribonucleases, is required for proper myogenesis.

Date: 2014
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DOI: 10.1038/ncomms5190

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