Abstract
Reversine is a synthetic molecule capable of inducing dedifferentiation of C2C12, a murine myoblast cell line, into multipotent progenitor cells, which can be redirected to differentiate in nonmuscle cell types under appropriate conditions. Reversine is also a potent inhibitor of Aurora B, a protein kinase required for mitotic chromosome segregation, spindle checkpoint function, cytokinesis and histone H3 phosphorylation, raising the possibility that the dedifferentiation capability of reversine is mediated through the inhibition of Aurora B. Indeed, here we show that several other well-characterized Aurora B inhibitors are capable of dedifferentiating C2C12 myoblasts. Significantly, expressing drug-resistant Aurora B mutants, which are insensitive to reversine block the dedifferentiation process, indicating that Aurora B kinase activity is required to maintain the differentiated state. We show that the inhibition of the spindle checkpoint or cytokinesis per se is not sufficient for dedifferentiation. Rather, our data support a model whereby changes in histone H3 phosphorylation result in chromatin remodeling, which in turn restores the multipotent state.
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Abbreviations
- ES:
-
embryonic stem cells
- ap2:
-
adipocyte fatty acid-binding protein
- LPL:
-
lipoprotein lipase
- ALP:
-
alkaline phosphatase
- NMMII:
-
nonmuscle myosin II heavy chain
- MEK:
-
mitogen-activated extracellular signal-regulated kinase
- ADM:
-
adipogenic-differentiating medium
- ODM:
-
osteogenic-differentiating medium
- MRFs:
-
muscle regulatory factors
- Id(s):
-
inhibitor of differentiation(s)
- Myf5:
-
myogenic factor 5
- Lys:
-
lysine
- Ser:
-
serine
- p:
-
phospho
- me:
-
methyl
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Acknowledgements
We are very grateful to Dr. Fabio Formiggini and to Dynamic Imaging Microscopy facility of CEINGE Biotecnologie Avanzate for the help with confocal microscopy. SST is a Cancer Research UK senior fellow.
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Amabile, G., D'Alise, A., Iovino, M. et al. The Aurora B kinase activity is required for the maintenance of the differentiated state of murine myoblasts. Cell Death Differ 16, 321–330 (2009). https://doi.org/10.1038/cdd.2008.156
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DOI: https://doi.org/10.1038/cdd.2008.156
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