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.

• Authors: Jae-Sung Kim, Eun Ju Kim, Jeong Su Oh, In-Chul Park, Sang-Gu Hwang
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 22 Pg. 6667-78 (Nov 15 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23983103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR

Chemical References

• Autoantigens
• CIP2A protein, human
• Cell Cycle Proteins
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Proto-Oncogene Proteins
• RNA, Small Interfering
• Protein Serine-Threonine Kinases

Topics

• Animals
• Autoantigens (physiology)
• Cell Cycle (drug effects, genetics)
• Cell Cycle Proteins (metabolism)
• Enzyme Activation (drug effects, genetics)
• Enzyme Stability (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• HeLa Cells
• Humans
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins (antagonists & inhibitors, physiology)
• Neoplasms (genetics, metabolism, pathology)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• RNA, Small Interfering (pharmacology)
• Sf9 Cells
• Spodoptera
• Polo-Like Kinase 1