Stathmin inhibition enhances okadaic acid-induced mitotic arrest - A potential role for stathmin in mitotic exit

Stathmin is a microtubule-destabilizing phosphoprotein that plays a critica l role in the regulation of mitosis. The microtubule-depolymerizing activit y of stathmin is lost upon phosphorylation in mitosis. Although the role of phosphorylation of stathmin by p34(cdc2) kinase in the assembly of the mit otic spindle is well established, the role of dephosphorylation of stathmin in mitosis is unknown. In this study, we tested the hypothesis that dephos phorylation of stathmin may be critically important for the depolymerizatio n of the mitotic spindle and the exit from mitosis. We compared the effects of okadaic acid, a specific inhibitor of serine/threonine protein phosphat ases, on different parameters of mitotic progression in the presence or abs ence of stathmin deficiency. Because okadaic acid prevents dephosphorylatio n of stathmin and results in accumulation of the inactive phosphorylated fo rm, exposure to okadaic acid would be expected to have a more profound effe ct on mitosis in the presence of relative stathmin deficiency. We found tha t inhibition of stathmin expression results in increased sensitivity to the antimitotic effects of okadaic acid. This was reflected by increased growt h inhibition associated with mitotic arrest. A vast majority of the stathmi n-inhibited cells were found to be arrested in late metaphase/anaphase and had severe mitotic spindle abnormalities. Exposure to okadaic acid also res ulted in a bigger ratio of polymerized/unpolymerized tubulin in stathmin-in hibited cells relative to control cells. Because the only difference betwee n the control and the stathmin-inhibited cells is the deficiency of stathmi n in the latter, the increased susceptibility of the stathmin-inhibited cel ls to okadaic acid-induced mitotic arrest implies a role for stathmin in th e later stages of mitosis.