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

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

^* To whom correspondence should be addressed. E-mail: daesiklim{at}kaist.ac.kr.

	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 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]

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

This article has been cited by other articles:

				S. J. Song, S. J. Kim, M. S. Song, and D.-S. Lim Aurora B-Mediated Phosphorylation of RASSF1A Maintains Proper Cytokinesis by Recruiting Syntaxin16 to the Midzone and Midbody Cancer Res., November 15, 2009; 69(22): 8540 - 8544. [Abstract] [Full Text] [PDF]