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

Oncogene volume 34, pages 3023–3035 (2015)Cite this article

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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.

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Acknowledgements

We are grateful for the critical reading and helpful discussion of members of the Deng laboratory. This work was supported in part by the Intramural Research Program of the NIDDK, NCI and CCR, NIH. DG is supported by 1R01CA152601-01 from the NCI, BC093803 from the DOD, SPORE P50CA98131 and a Hirshberg Foundation for Pancreatic Cancer Research Seed Grant Award. Melissa Stauffer, PhD, of Scientific Editing Solutions, provided editorial assistance.

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Authors and Affiliations

  1. Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    A Vassilopoulos, Y Tominaga, H-Seok Kim, T Lahusen & C-X Deng

  2. Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    A Vassilopoulos & D Gius

  3. Department of Life Science, Ewha Womans University, Seoul, South Korea

    H-Seok Kim

  4. Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA

    B Li & H Yu

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  1. A Vassilopoulos
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Correspondence to C-X Deng.

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Vassilopoulos, A., Tominaga, Y., Kim, HS. et al. WEE1 murine deficiency induces hyper-activation of APC/C and results in genomic instability and carcinogenesis. Oncogene 34, 3023–3035 (2015). https://doi.org/10.1038/onc.2014.239

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