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Nat Commun. 2014 Jun 27;5:4190. doi: 10.1038/ncomms5190.

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

Author information

1
1] Department of Biochemistry, Goodman Cancer Center, McGill University, McIntyre Building Room 915B, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6 [2] INSERM, UMR 1037, Centre de Recherche en Cancérologie de Toulouse, 31432 Toulouse, France.
2
Department of Biochemistry, Goodman Cancer Center, McGill University, McIntyre Building Room 915B, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.
3
Spanish National Cancer Research Centre (CNIO) Telomeres and Telomerase Group, Molecular Oncology Program, C/ Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
4
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682, USA.
5
Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A2B4.
6
National Institute on Aging, National Institutes of Health, Biomedical Research Center, Room 06C226, 251 Bayview Boulevard, Suite 100, Baltimore, Maryland 21224-6825, USA.
7
INSERM, UMR 1037, Centre de Recherche en Cancérologie de Toulouse, 31432 Toulouse, France.
8
Istituto Nazionale Ricerca sul Cancro (IST), Laboratory of Gene Expression Regulation, c/o CBA Building A3, Room 30, Largo R. Benzi, 10, 16132 Genova, Italy.

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.

PMID:
24969639
PMCID:
PMC4074165
DOI:
10.1038/ncomms5190
[Indexed for MEDLINE]
Free PMC Article

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