Overexpression of EVI1 interferes with cytokinesis and leads to accumulation of cells with supernumerary centrosomes in G0/1 phase

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Kadin Karakaya - , German Cancer Research Center (DKFZ), Heidelberg University  (Author)
  • Friederike Herbst - , German Cancer Research Center (DKFZ) (Author)
  • Claudia Ball - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Hanno Glimm - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Alwin Krämer - , German Cancer Research Center (DKFZ), Heidelberg University  (Author)
  • Harald Löffler - , German Cancer Research Center (DKFZ), Heidelberg University  (Author)

Abstract

Ectopic viral integration site 1 (EVI1), a transcription factor frequently overexpressed in myeloid neoplasias, has been implicated in the generation of malignancy-associated centrosomal aberrations and chromosomal instability. Here, we sought to investigate the underlying cause of centrosome amplification in EVI1-overexpressing cells. We found that overexpression of EVI1-HA in U2OS cells induced supernumerary centrosomes, which were consistently associated with enlarged nuclei or binuclear cells. Live cell imaging experiments identified cytokinesis failure as the underlying cause of this phenotype. In accordance with previous reports, EVI1 overexpression induced a partial cell cycle arrest in G0/1phase, accompanied by elevated cyclin D1 and p21 levels, reduced Cdk2 activity and activation of the p53 pathway. Supernumerary centrosomes predominantly occurred in resting cells, as identified by low levels of the proliferation marker Ki-67, leading to the conclusion that they result from tetraploidization after cytokinesis failure and are confined to G0/1-arrested tetraploid cells. Depletion of p53 using siRNA revealed that further polyploidization of these cells was inhibited by the p53-dependent tetraploidy checkpoint.

Details

Original languageEnglish
Pages (from-to)3492-3503
Number of pages12
JournalCell Cycle
Volume11
Issue number18
Publication statusPublished - 15 Sept 2012
Peer-reviewedYes
Externally publishedYes

External IDs

PubMed 22894935

Keywords

Keywords

  • Centrosome amplification, Chromosomal instability, Cytokinesis, EVI1, Mitosis