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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.
