Ckap2 Regulates Aneuploidy, Cell Cycling, and Cell Death in a p53-Dependent Manner

Katsuya Tsuchihara,Christopher D Richardson,Lauren Brown,Annick Itie-Youten,Tak Wah Mak,Robert Rottapel,Christopher Bakal,Masami Hirota-Tsuchihara,Marees Harris-Brandts,Kathrin Zaugg,Hitoshi Okada,Samuel Benchimol,Alexandra Ho,Valentina Lapin

doi:10.1158/0008-5472.can-04-4223

Abstract

We used DNA microarray screening to identify Ckap2 (cytoskeleton associated protein 2) as a novel p53 target gene in a mouse erythroleukemia cell line. DNA damage induces human and mouse CKAP2 expression in a p53-dependent manner and p53 activates the Ckap2 promoter. Overexpressed Ckap2 colocalizes with and stabilizes microtubules. In p53-null cells, overexpression of Ckap2 induces tetraploidy with aberrant centrosome numbers, suggesting disturbed mitosis and cytokinesis. In p53-competent cells, Ckap2 does not induce tetraploidy but activates p53-mediated cell cycle arrest and apoptosis. Our data suggest the existence of a functional positive feedback loop in which Ckap2 activates the G1 tetraploidy checkpoint and prevents aneuploidy.

Highlights

Inactivation of the tumor suppressor p53 is commonly associated with tumorigenesis. p53 prevents the proliferation of aberrant cells by regulating the cell cycle and apoptosis
Recent evidence suggests that DNA-damaging agents activate a small subset of common target genes, but that p53 induces a unique constellation of genes depending on the stimulus [2]
Ckap2, which we identified as a novel p53 target gene whose product colocalizes with microtubules, may be such a stimulusspecific target gene

Summary

Introduction

Inactivation of the tumor suppressor p53 is commonly associated with tumorigenesis. p53 prevents the proliferation of aberrant cells by regulating the cell cycle and apoptosis. P53 prevents the proliferation of aberrant cells by regulating the cell cycle and apoptosis. Once activated by DNA damage, p53 translocates into the nucleus and induces the transcription of target genes harboring p53-binding sites. Tumor-derived mutant p53 proteins lack transactivation ability, confirming the importance of p53 target genes in tumor prevention [1]. Whereas many p53 target genes are known, transcriptomic and bioinformatic studies suggest that p53 induces additional genes important for tumor suppression [2, 3]. Aneuploidy is linked to genetic instability and malignant tumor progression. The mechanism is not fully elucidated, p53 is frequently activated in tetraploid cells and prevents the proliferation of these cells by inducing their G1 arrest or apoptosis [4,5,6]

Methods

Results

Conclusion