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Molecular and Cellular Biology, January 2004, p. 514-526, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.514-526.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mitotic Degradation of Human Thymidine Kinase 1 Is Dependent on the Anaphase-Promoting Complex/Cyclosome-Cdh1-Mediated Pathway

Po-Yuan Ke and Zee-Fen Chang*

Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan (Republic of China)

Received 10 July 2003/ Returned for modification 21 August 2003/ Accepted 21 October 2003

The expression of human thymidine kinase 1 (hTK1) is highly dependent on the growth states and cell cycle stages in mammalian cells. The amount of hTK1 is significantly increased in the cells during progression to the S and M phases, and becomes barely detectable in the early G1 phase by a proteolytic control during mitotic exit. This tight regulation is important for providing the correct pool of dTTP for DNA synthesis at the right time in the cell cycle. Here, we investigated the mechanism responsible for mitotic degradation of hTK1. We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. Furthermore, a KEN box sequence located in the C-terminal region of hTK1 is required for its mitotic degradation and interaction capability with Cdh1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif. Taken together, we concluded that activation of the APC/C-Cdh1 complex during mitotic exit controls timing of hTK1 destruction, thus effectively minimizing dTTP formation from the salvage pathway in the early G1 phase of the cell cycle in mammalian cells.

* Corresponding author. Mailing address: Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University, College of Medicine, No. 1, Section 1, Jen-Ai Road, Taipei, Taiwan, Republic of China. Fax: 886-2-2395-8904. E-mail: ZFCHANG{at}ha.mc.ntu.edu.tw.

Molecular and Cellular Biology, January 2004, p. 514-526, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.514-526.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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