Aurora A regulates prometaphase progression by inhibiting the ability of RASSF1A to suppress APC-Cdc20 activity.
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.
Song
Su Jung
SJ
National Research Laboratory for Genomic Stability, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Song
Min Sup
MS
Kim
Soon Jung
SJ
Kim
So Yeon
SY
Kwon
Seung Hae
SH
Kim
Jhin Gook
JG
Calvisi
Diego F
DF
Kang
Dongmin
D
Lim
Dae-Sik
DS
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
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