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J. Biol. Chem., Vol. 278, Issue 4, 2541-2548, January 24, 2003

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Citron Kinase Is a Cell Cycle-dependent, Nuclear Protein Required for G₂/M Transition of Hepatocytes^*

Huifei Liu, Ferdinando Di Cunto^§, Sara Imarisio^§, and Lola M. Reid^¶

From the  Department of Cell and Molecular Physiology and the ^¶ Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 and the ^§ Department of Genetics, Biology, and Biochemistry, University of Torino, 10126 Torino, Italy

Citron Kinase (Citron-K) is a cell cycle-dependent protein regulating the G₂/M transition in hepatocytes. Synchronization studies demonstrated that expression of the Citron-K protein starts at the late S and/or the early G₂ phase after that of cyclin B1. Expression of Citron-K is developmentally regulated. Levels of Citron-K mRNA and protein are highest in embryonic liver and gradually decrease after birth. Citron-K exists in interphase nuclei and begins to disperse into the cytoplasm at prophase. It concentrates at the cleavage furrow and midbody during anaphase, telophase, and cytokinesis, implicating a role in the control of cytokinesis. However, studies with knockouts show that Citron-K is not essential for cytokinesis in hepatocytes. Instead, loss of Citron-K causes a significant increase of G₂ tetraploid nuclei in one-week-old rat and mouse liver. In addition, Citron-K deficiency triggers apoptosis in a small subset of embryonic liver cells. In summary, our data demonstrate that Citron-K has a distinct cell cycle-dependent expression pattern and cellular localization as a downstream target of Rho-GTPase and functions in the control of G₂/M transition in the hepatocyte cell cycle.

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