WEE1 murine deficiency induces hyper-activation of APC/C and results in genomic instability and carcinogenesis

A. Vassilopoulos, Y. Tominaga, H. Seok Kim, T. Lahusen, B. Li, H. Yu, D. Gius, C. X. Deng

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The tyrosine kinase WEE1 controls the timing of entry into mitosis in eukaryotes and its genetic deletion leads to pre-implantation lethality in mice. Here, we show that besides the premature mitotic entry phenotype, Wee1 mutant murine cells fail to complete mitosis properly and exhibit several additional defects that contribute to the deregulation of mitosis, allowing mutant cells to progress through mitosis at the expense of genomic integrity. WEE1 interacts with the anaphase promoting complex, functioning as a negative regulator, and the deletion of Wee1 results in hyper-activation of this complex. Mammary specific knockout mice overcome the DNA damage response pathway triggered by the mis-coordination of the cell cycle in mammary epithelial cells and heterozygote mice spontaneously develop mammary tumors. Thus, WEE1 functions as a haploinsufficient tumor suppressor that coordinates distinct cell division events to allow correct segregation of genetic information into daughter cells and maintain genome integrity.

Original languageEnglish (US)
Pages (from-to)3023-3035
Number of pages13
JournalOncogene
Volume34
Issue number23
DOIs
StatePublished - Jun 4 2015

Fingerprint

Genomic Instability
Mitosis
Carcinogenesis
Breast
Anaphase-Promoting Complex-Cyclosome
Heterozygote
Eukaryota
Knockout Mice
Cell Division
Protein-Tyrosine Kinases
DNA Damage
Cell Cycle
Epithelial Cells
Genome
Breast Neoplasms
Phenotype
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

WEE1 murine deficiency induces hyper-activation of APC/C and results in genomic instability and carcinogenesis. / Vassilopoulos, A.; Tominaga, Y.; Kim, H. Seok; Lahusen, T.; Li, B.; Yu, H.; Gius, D.; Deng, C. X.

In: Oncogene, Vol. 34, No. 23, 04.06.2015, p. 3023-3035.

Research output: Contribution to journalArticle

Vassilopoulos, A, Tominaga, Y, Kim, HS, Lahusen, T, Li, B, Yu, H, Gius, D & Deng, CX 2015, 'WEE1 murine deficiency induces hyper-activation of APC/C and results in genomic instability and carcinogenesis', Oncogene, vol. 34, no. 23, pp. 3023-3035. https://doi.org/10.1038/onc.2014.239
Vassilopoulos, A. ; Tominaga, Y. ; Kim, H. Seok ; Lahusen, T. ; Li, B. ; Yu, H. ; Gius, D. ; Deng, C. X. / WEE1 murine deficiency induces hyper-activation of APC/C and results in genomic instability and carcinogenesis. In: Oncogene. 2015 ; Vol. 34, No. 23. pp. 3023-3035.
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