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Molecular and Cellular Biology, June 2009, p. 2935-2944, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01837-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

TTK/hMps1 Mediates the p53-Dependent Postmitotic Checkpoint by Phosphorylating p53 at Thr18{triangledown} ,{dagger}

Yi-Fu Huang,1,2 Margaret Dah-Tsyr Chang,1 and Sheau-Yann Shieh2*

Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300, Taiwan,1 Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan2

Received 3 December 2008/ Returned for modification 31 December 2008/ Accepted 23 March 2009

Upon prolonged arrest in mitosis, cells undergo adaptation and exit mitosis without cell division. These tetraploid cells are either eliminated by apoptosis or arrested in the subsequent G1 phase in a spindle checkpoint- and p53-dependent manner. p53 has long been known to be activated by spindle poisons, such as nocodazole and Taxol, although the underlying mechanism remains elusive. Here we present evidence that stabilization and activation of p53 by spindle disruption requires the spindle checkpoint kinase TTK/hMps1. TTK/hMps1 phoshorylates the N-terminal domain of p53 at Thr18, and this phosphorylation disrupts the interaction with MDM2 and abrogates MDM2-mediated p53 ubiquitination. Phosphorylation at Thr18 enhances p53-dependent activation of not only p21 but also Lats2, two mediators of the postmitotic checkpoint. Furthermore, a phospho-mimicking substitution at Thr18 (T18D) is more competent than the phospho-deficient mutant (T18A) in rescuing the tetraploid checkpoint defect of p53-depleted cells. Our findings therefore provide a mechanism connecting the spindle checkpoint with p53 in the maintenance of genome stability.

* Corresponding author. Mailing address: Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2 Academia Road, Taipei 115, Taiwan. Phone: 886-2-26523916. Fax: 886-2-27829143, E-mail: sy88{at}ibms.sinica.edu.tw

{triangledown} Published ahead of print on 30 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2009, p. 2935-2944, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01837-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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