Abstract
Abnormal cell-cycle control can lead to aberrant cell proliferation and cancer. The oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) is an inhibitor of protein phosphatase 2A (PP2A) that stabilizes c-Myc. However, the precise role of CIP2A in cell division is not understood. Herein, we show that CIP2A is required for mitotic progression by regulating the polo-like kinase (Plk1). With mitotic entry, CIP2A translocated from the cytoplasm to the nucleus, where it was enriched at spindle poles. CIP2A depletion delayed mitotic progression, resulting in mitotic abnormalities independent of PP2A activity. Unexpectedly, CIP2A interacted directly with the polo-box domain of Plk1 during mitosis. This interaction was required to maintain Plk1 stability by blocking APC/C-Cdh1-dependent proteolysis, thereby enhancing the kinase activity of Plk1 during mitosis. We observed strong correlation and in vivo interactions between these two proteins in multiple human cancer specimens. Overall, our results established a novel function for CIP2A in facilitating the stability and activity of the pivotal mitotic kinase Plk1 in cell-cycle progression and tumor development.
Highlights
Proper cell-cycle progression involves coordination of multiple events, such as chromosome condensation, spindle formation, chromosome segregation, and cytokinesis, and is tightly controlled by posttranslational modifications such as phosphorylation and ubiquitination [1, 2]
Regulation of cancerous inhibitor of protein phosphatase 2A (CIP2A) during cell-cycle progression To investigate the role of CIP2A in cell division, we first examined CIP2A protein expression during different phases of the cell cycle in HeLa cells synchronized by using a double thymidine and thymidine–nocodazole block protocol (Fig. 1A)
Most of the CIP2A protein expressed was localized in the cytoplasm during interphase, and, as cells passed from the S-phase to the G2–M phase, CIP2A was initially concentrated in the pericentrosomal region and clearly localized at spindle poles during mitosis, as shown by immunofluorescence analysis (Fig. 1B)
Summary
Proper cell-cycle progression involves coordination of multiple events, such as chromosome condensation, spindle formation, chromosome segregation, and cytokinesis, and is tightly controlled by posttranslational modifications such as phosphorylation and ubiquitination [1, 2]. Mitotic kinases, including cyclin-dependent kinase 1, polo-like kinases (Plk), and Aurora kinases, phosphorylate their substrates during mitotic progression. Components of the ubiquitin–proteasome system, such as the anaphase-promoting complex/cyclosome (APC/C), in turn directs the ordered destruction of critical mitotic substrates (i.e., spindle assembly checkpoint proteins) and mitotic kinases [1, 2]. Plk plays a crucial role in multiple steps of mitosis, including the G2–M transition, centrosome maturation, bipolar spindle formation, chromosome segregation, and cytokinesis [3, 4]. Plk contains an N-terminal kinase domain and a C-terminal polo-box domain (PBD) that have been implicated in regulating kinase activity and subcellular localization [3, 4]
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