title: TTK/hMps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at Thr18.
abstract: 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 G(1) 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.
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Yi-Fu
authors.initials: YF
authors.lastname: Huang
authors.forename: Margaret Dah-Tsyr
authors.initials: MD
authors.lastname: Chang
authors.forename: Sheau-Yann
authors.initials: SY
authors.lastname: Shieh