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

¹ National Research Laboratory for Genomic Stability, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea; ² Bioimaging Team, Korea Basic Science Institute, Chuncheon, Gangwon-Do, Korea; ³ Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and ⁴ Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy

Requests for reprints: Dae-Sik Lim, Korea Advanced Institute of Science and Technology, Yuesung, Daejeon 305701, Korea. Phone: 82-42-350-2635; Fax: 82-42-350-2610; E-mail: daesiklim{at}kaist.ac.kr.

Key Words: RASSF1A • Aurora kinases • tumor suppressor • mitotic progression • tumorigenesis

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 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 up-regulated 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