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

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.

• Authors: 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, Sander van den Heuvel
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 5906 (Jan 06 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 25562820 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Caenorhabditis elegans Proteins
• Cdh1 Proteins
• Cyclin D
• FZR1 protein, human
• Multiprotein Complexes
• Repressor Proteins
• Retinoblastoma Protein
• lin-35 protein, C elegans
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Animals
• Base Sequence
• Caenorhabditis elegans
• Caenorhabditis elegans Proteins (genetics)
• Cdh1 Proteins (genetics, metabolism)
• Cell Cycle (physiology)
• Cell Line, Tumor
• Cyclin D (metabolism)
• Cyclin-Dependent Kinase 4 (metabolism)
• Cyclin-Dependent Kinase 6 (metabolism)
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• Immunoprecipitation
• Mass Spectrometry
• Microscopy, Fluorescence
• Molecular Sequence Data
• Multiprotein Complexes (metabolism)
• Repressor Proteins (genetics)
• Retinoblastoma Protein (genetics, metabolism)
• Sequence Analysis, DNA