title: Aurora A regulates prometaphase progression by inhibiting the ability of RASSF1A to suppress APC-Cdc20 activity.
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.
authors.affiliation: National Research Laboratory for Genomic Stability, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Song
authors.forename: Min Sup
authors.initials: MS
authors.lastname: Song
authors.forename: Soon Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Seung Hae
authors.initials: SH
authors.lastname: Kwon
authors.forename: Jhin Gook
authors.initials: JG
authors.lastname: Kim
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.forename: Dongmin
authors.initials: D
authors.lastname: Kang
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
mesh_terms: D064127:Aurora Kinases; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D016195:G2 Phase / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008938:Mitosis / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D049468:Prometaphase / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C411762:RASSF1 protein, human; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C577488:CDC20 protein, human; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases