Aurora A Regulates Prometaphase Progression by Inhibiting the Ability of RASSF1A to Suppress APC-Cdc20 Activity

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The Aurora (Ip1) kinase family plays important roles in the regulation of mitosis and tumorigenesis. The tumor suppressor RASSF1A controls mitotic progression by regulating anaphase-promoting complex (APC)-Cdc20 activity and microtubule stability, but the mechanism by which this action is regulated has not been previously established. Here, we show that Aurora A and B associate with and phosphorylate RASSF1A on serine 203 in vivo at different times and in different subcellular compartments during mitosis. Notably, both depletion of Aurora A by RNA interference and expression of a nonphosphorylatable RASSF1A (S203A) mutant gene led to a marked delay in prometaphase progression. This is likely because of the failure of RASSF1A to dissociate from Cdc20, constitutive inhibition of APC-Cdc20, and accumulation of mitotic cyclins. In contrast, the delay in prometaphase progression caused by Aurora A depletion was largely normalized by phosphomimetic RASSF1A (S203D). Finally, RASSF1A phosphorylation on serine 203 was upregulated in Aurora A-overexpressing human tumors. These findings indicate that Aurora A plays a critical role in RASSF1A-APC-Cdc20 regulatory mechanisms that control normal prometaphase progression and that are involved in tumorigenesis. [Cancer Res 2009;69(6):2314-23]
Publisher
AMER ASSOC CANCER RESEARCH
Issue Date
2009-03
Language
English
Article Type
Article
Keywords

ANAPHASE-PROMOTING COMPLEX; SPINDLE ASSEMBLY CHECKPOINT; SMALL-MOLECULE INHIBITOR; TUMOR-SUPPRESSOR; A KINASE; MICROTUBULE STABILITY; MITOTIC ENTRY; MITOSIS; PROTEIN; DEGRADATION

Citation

CANCER RESEARCH, v.69, no.6, pp.2314 - 2323

ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-08-3984
URI
http://hdl.handle.net/10203/97419
Appears in Collection
BS-Journal Papers(저널논문)
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