Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells

Inge The, Suzan Ruijtenberg, Benjamin P. Bouchet, Alba Cristobal, Martine B. W. Prinsen, Tim van Mourik, John Koreth, Huihong Xu, Albert J. R. Heck, Anna Akhmanova, Edwin Cuppen, Mike Boxem, Javier Muñoz and Sander van den Heuvel ()
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Inge The: Developmental Biology, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
Suzan Ruijtenberg: Developmental Biology, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
Benjamin P. Bouchet: Cell Biology, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands
Alba Cristobal: Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University
Martine B. W. Prinsen: Developmental Biology, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
Tim van Mourik: Developmental Biology, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
John Koreth: Hematologic Oncology, Dana-Farber Cancer Institute
Huihong Xu: Boston University School of Medicine and Boston Medical Center
Albert J. R. Heck: Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University
Anna Akhmanova: Cell Biology, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands
Edwin Cuppen: Hubrecht Institute
Mike Boxem: Developmental Biology, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
Javier Muñoz: Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University
Sander van den Heuvel: Developmental Biology, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry. Most human cancers contain overactive CDK4/6-cyclin D, and CDK4/6-specific inhibitors are promising anti-cancer therapeutics. Here, we investigate the critical functions of CDK4/6-cyclin D kinases, starting from an unbiased screen in the nematode Caenorhabditis elegans. We found that simultaneous mutation of lin-35, a retinoblastoma (Rb)-related gene, and fzr-1, an orthologue to the APC/C co-activator Cdh1, completely eliminates the essential requirement of CDK4/6-cyclin D (CDK-4/CYD-1) in C. elegans. CDK-4/CYD-1 phosphorylates specific residues in the LIN-35 Rb spacer domain and FZR-1 amino terminus, resembling inactivating phosphorylations of the human proteins. In human breast cancer cells, simultaneous knockdown of Rb and FZR1 synergistically bypasses cell division arrest induced by the CDK4/6-specific inhibitor PD-0332991. Our data identify FZR1 as a candidate CDK4/6-cyclin D substrate and point to an APC/CFZR1 activity as an important determinant in response to CDK4/6-inhibitors.

Date: 2015
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DOI: 10.1038/ncomms6906

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