CIP2A Modulates Cell-Cycle Progression in Human Cancer Cells by Regulating the Stability and Activity of Plk1

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. Cancer Res; 73(22); 6667-78. Ó2013 AACR.

Plk1 inhibition leads to a failure of mitotic division during the first mitotic division in pig embryos

“…Plk1 is a serine/threonine protein kinase that represents a mitotic target due to its important role in centrosome maturation [16], bipolar spindle formation [17], and other functions. Overexpression of Plk1 has been commonly detected in tumors.…”

Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target

“…In addition, CIP2A promotes progenitor cell self-renewal and protects cancer cells from therapy-induced apoptosis or senescence induction (6,(16)(17)(18)(19). Furthermore, the role of CIP2A in regulation of cell cycle and mitosis was demonstrated by a recent study identifying PLK1 as a target of CIP2A (20). Importantly, several independent studies have demonstrated that CIP2A depletion via small interfering RNAs (siRNA) inhibits the growth of xenografted tumors of various cancer cell types (4,11,15).…”

Leucine-rich repeat-containing protein 59 mediates nuclear import of cancerous inhibitor of PP2A in prostate cancer cells

“…Though CIP2A was first described to interact with and inhibit PP2A activity, recent work has led to the identification of novel CIP2A protein partners [27,28] whose activities suggest that CIP2A may regulate mitosis independent of its interaction with PP2A. Jeong et al demonstrated that CIP2A interacts with and enhances NIMA-related kinase 2 (NEK2) activity during G2/M to promote centrosome separation [27].…”