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.
Highlights
Mitosis is the fundamental process by which duplicated chromosomes are divided into two daughter cells [1]
A coimmunoprecipitation analysis of HeLa cell lysates obtained at various stages of mitosis revealed that endogenous RASSF1A interacts with endogenous Aurora A during early mitosis and with Aurora B during late mitosis (Fig. 1A)
We found that reintroducing RASSF1A (S203A) mutant into RASSF1AÀ/À mouse embryonic fibroblasts (MEF) led to a profound elongation of mitosis accompanied by accumulation of cyclins A and B compared with wild-type cells (Fig. 3A)
Summary
Mitosis is the fundamental process by which duplicated chromosomes are divided into two daughter cells [1]. Aurora kinases regulate cell cycle progression from G2 phase to cytokinesis in a coordinated manner [1,2,3]. Aurora A contributes to centrosome maturation and the establishment of spindle bipolarity by phosphorylating several substrates, including Eg5, TACC, CENPA, and Ajuba [4,5,6,7]. Aurora A localizes to centrosomes during interphase and to spindle poles and fibers from prometaphase to anaphase [3]. Aurora B plays an important role in chromosome segregation and cytokinesis by phosphorylating INCENP, MKLP-1
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