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Sci Rep. 2017 Sep 14;7(1):11503. doi: 10.1038/s41598-017-11917-3.

Evasion of regulatory phosphorylation by an alternatively spliced isoform of Musashi2.

Author information

1
University of Arkansas for Medical Sciences, Department of Neurobiology and Developmental Sciences, 4301 W. Markham, Little Rock, 72205, AR, USA.
2
University of Arkansas for Medical Science, Center for Translational Neuroscience, 4301 W. Markham, Little Rock, 72205, AR, USA.
3
University of Arkansas for Medical Sciences, Department of Pharmaceutical Sciences, 4301 W. Markham, Little Rock, 72205, AR, USA.
4
Department of Orthopedics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510182, PR China.
5
University of Arkansas for Medical Sciences, Department of Physiology and Biophysics, 4301 W. Markham, Little Rock, 72205, AR, USA.
6
Center for Genomic Regulation, Department of Gene Regulation, Stem Cells and Cancer, C/Dr. Aiguader 88, 08003, Barcelona, Spain.
7
University of Arkansas for Medical Sciences, Department of Biomedical Informatics, 4301 W. Markham, Little Rock, 72205, AR, USA.
8
MRC Toxicology Unit, Lancaster Road, Leicester, UK.
9
University of Arkansas for Medical Sciences, Department of Neurobiology and Developmental Sciences, 4301 W. Markham, Little Rock, 72205, AR, USA. Angus@UAMS.edu.
10
Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR, 72205, United States. Angus@UAMS.edu.

Abstract

The Musashi family of RNA binding proteins act to promote stem cell self-renewal and oppose cell differentiation predominantly through translational repression of mRNAs encoding pro-differentiation factors and inhibitors of cell cycle progression. During tissue development and repair however, Musashi repressor function must be dynamically regulated to allow cell cycle exit and differentiation. The mechanism by which Musashi repressor function is attenuated has not been fully established. Our prior work indicated that the Musashi1 isoform undergoes site-specific regulatory phosphorylation. Here, we demonstrate that the canonical Musashi2 isoform is subject to similar regulated site-specific phosphorylation, converting Musashi2 from a repressor to an activator of target mRNA translation. We have also characterized a novel alternatively spliced, truncated isoform of human Musashi2 (variant 2) that lacks the sites of regulatory phosphorylation and fails to promote translation of target mRNAs. Consistent with a role in opposing cell cycle exit and differentiation, upregulation of Musashi2 variant 2 was observed in a number of cancers and overexpression of the Musashi2 variant 2 isoform promoted cell transformation. These findings indicate that alternately spliced isoforms of the Musashi protein family possess distinct functional and regulatory properties and suggest that differential expression of Musashi isoforms may influence cell fate decisions.

PMID:
28912529
PMCID:
PMC5599597
DOI:
10.1038/s41598-017-11917-3
[Indexed for MEDLINE]
Free PMC Article

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