Aneugenic activity of Op18/stathmin is potentiated by the somatic Q18-->e mutation in leukemic cells.
Op18/stathmin (Op18) is a phosphorylation-regulated microtubule destabilizer that is frequently overexpressed in tumors. The importance of Op18 in malignancy was recently suggested by identification of a somatic Q18-->E mutation of Op18 in an adenocarcinoma. We addressed the functional consequences of aberrant Op18 expression in leukemias by analyzing the cell cycle of K562 cells either depleted of Op18 by expression of interfering hairpin RNA or induced to express wild-type or Q18E substituted Op18. We show here that although Op18 depletion increases microtubule density during interphase, the density of mitotic spindles is essentially unaltered and cells divide normally. This is consistent with phosphorylation-inactivation of Op18 during mitosis. Overexpression of wild-type Op18 results in aneugenic activities, manifest as aberrant mitosis, polyploidization, and chromosome loss. One particularly significant finding was that the aneugenic activity of Op18 was dramatically increased by the Q18-->E mutation. The hyperactivity of mutant Op18 is apparent in its unphosphorylated state, and this mutation also suppresses phosphorylation-inactivation of the microtubule-destabilizing activity of Op18 without any apparent effect on its phosphorylation status. Thus, although Op18 is dispensable for mitosis, the hyperactive Q18-->E mutant, or overexpressed wild-type Op18, exerts aneugenic effects that are likely to contribute to chromosomal instability in tumors.
Holmfeldt
Per
P
Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden.
Brännström
Kristoffer
K
Stenmark
Sonja
S
Gullberg
Martin
M
D024422:Aneugens / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D043171:Chromosomal Instability; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000235:genetics; D009154:Mutation; D010766:Phosphorylation; D034622:RNA Interference; D008941:Spindle Apparatus / Q000378:metabolism*; D050777:Stathmin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
D024422:Aneugens; D050777:Stathmin; D014404:Tubulin