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Oncogene. 2015 Jun 4;34(23):3023-35. doi: 10.1038/onc.2014.239. Epub 2014 Aug 4.

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

Author information

1
1] Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA [2] Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
2
Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
3
1] Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA [2] Department of Life Science, Ewha Womans University, Seoul, South Korea.
4
Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
5
Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

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.

PMID:
25088202
PMCID:
PMC5547996
DOI:
10.1038/onc.2014.239
[Indexed for MEDLINE]
Free PMC Article

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