Publication: Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells
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2015-01-06
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Nature Publishing Group
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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/C(FZR1) activity as an important determinant in response to CDK4/6-inhibitors.
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Animals Base Sequence Caenorhabditis elegans Caenorhabditis elegans Proteins Cdh1 Proteins Cell Cycle Cell Line, Tumor Cyclin D Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase 6 Gene Knockdown Techniques HEK293 Cells Humans Immunoprecipitation Mass Spectrometry Microscopy, Fluorescence Molecular Sequence Data Multiprotein Complexes Repressor Proteins Retinoblastoma Protein Sequence Analysis, DNA
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Nat Commun. 2015 Jan 6;6:5906.