Aurora a regulates prometaphase progression by inhibiting the ability of RASSF1A to suppress APC-Cdc20 activity

Su Jung Song, Min Sup Song, Soon Jung Kim, So Yeon Kim, Seung Hae Kwon, Jhin Gook Kim, Diego F. Calvisi, Dongmin Kang, Dae Sik Lim

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

The Aurora (Ipl) 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 UNA interference and expression of a nonphosphorylatable KASSF1A (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, BASSF1A phosphorylation on serine 203 was up- regulated in Aurora A-overexpressing human tumors. These findings indicate that Aurora A plays a critical role in RASSFlA-APC-Cdc20 regulatory mechanisms that control normal prometaphase progression and that are involved in tumorigenesis.

Original languageEnglish
Pages (from-to)2314-2323
Number of pages10
JournalCancer Research
Volume69
Issue number6
DOIs
StatePublished - 15 Mar 2009

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