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 critical role in the regulation of mitosis. The microtubule-depolymerizing activity of stathmin is lost upon phosphorylation in mitosis. Although the role of phosphorylation of stathmin by p34(cdc2) kinase in the assembly of the mitotic spindle is well established, the role of dephosphorylation of stathmin in mitosis is unknown. In this study, we tested the hypothesis that dephosphorylation of stathmin may be critically important for the depolymerization of the mitotic spindle and the exit from mitosis. We compared the effects of okadaic acid, a specific inhibitor of serine/threonine protein phosphatases, on different parameters of mitotic progression in the presence or absence of stathmin deficiency. Because okadaic acid prevents dephosphorylation of stathmin and results in accumulation of the inactive phosphorylated form, exposure to okadaic acid would be expected to have a more profound effect on mitosis in the presence of relative stathmin deficiency. We found that inhibition of stathmin expression results in increased sensitivity to the antimitotic effects of okadaic acid. This was reflected by increased growth inhibition associated with mitotic arrest. A vast majority of the stathmin-inhibited cells were found to be arrested in late metaphase/anaphase and had severe mitotic spindle abnormalities. Exposure to okadaic acid also resulted in a bigger ratio of polymerized/unpolymerized tubulin in stathmin-inhibited cells relative to control cells. Because the only difference between the control and the stathmin-inhibited cells is the deficiency of stathmin in the latter, the increased susceptibility of the stathmin-inhibited cells to okadaic acid-induced mitotic arrest implies a role for stathmin in the later stages of mitosis.
Mistry
S J
SJ
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Atweh
G F
GF
D002453:Cell Cycle / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D008868:Microtubule Proteins; D008870:Microtubules / Q000502:physiology; D008938:Mitosis / Q000187:drug effects*; D019319:Okadaic Acid / Q000494:pharmacology*; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D050777:Stathmin
D008868:Microtubule Proteins; D010750:Phosphoproteins; C493995:STMN1 protein, human; D050777:Stathmin; D019319:Okadaic Acid