Cyclin D1 Stability Is Partly Controlled by O -GlcNAcylation

Cyclin D1 is the regulatory partner of the cyclin-dependent kinases (CDKs) CDK4 or CDK6. Once associated and activated, the cyclin D1/CDK complexes drive the cell cycle entry and G1 phase progression in response to extracellular signals. To ensure their timely and accurate activation during cell cyc...

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Published inFrontiers in endocrinology (Lausanne) Vol. 10; p. 106
Main Authors Masclef, Louis, Dehennaut, Vanessa, Mortuaire, Marlène, Schulz, Céline, Leturcq, Maïté, Lefebvre, Tony, Vercoutter-Edouart, Anne-Sophie
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers 22.02.2019
Frontiers Media S.A
Subjects
Biochemistry
Biochemistry, Molecular Biology
Cancer
cell cycle
Cellular Biology
cyclin D
Endocrinology
Life Sciences
O-GlcNAc
stability
Subcellular Processes
ubiquitination
cyclin D
cell cycle
ubiquitination
O-GlcNAc
stability
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Summary:Cyclin D1 is the regulatory partner of the cyclin-dependent kinases (CDKs) CDK4 or CDK6. Once associated and activated, the cyclin D1/CDK complexes drive the cell cycle entry and G1 phase progression in response to extracellular signals. To ensure their timely and accurate activation during cell cycle progression, cyclin D1 turnover is finely controlled by phosphorylation and ubiquitination. Here we show that the dynamic and reversible linked β-N-Acetyl-glucosaminylation ( -GlcNAcylation) regulates also cyclin D1 half-life. High -GlcNAc levels increase the stability of cyclin D1, while reduction of -GlcNAcylation strongly decreases it. Moreover, elevation of -GlcNAc levels through -GlcNAcase (OGA) inhibition significantly slows down the ubiquitination of cyclin D1. Finally, biochemical and cell imaging experiments in human cancer cells reveal that the -GlcNAc transferase (OGT) binds to and glycosylates cyclin D1. We conclude that -GlcNAcylation promotes the stability of cyclin D1 through modulating its ubiquitination.
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PMCID: PMC6395391
Present Address: Louis Masclef, Department of Medicine, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montreal, QC, Canada
Edited by: Xiaoyong Yang, School of Medicine, Yale University, United States
Reviewed by: Michael Boyce, Duke University, United States; Chad Slawson, University of Kansas Medical Center Research Institute, United States
This article was submitted to Molecular and Structural Endocrinology, a section of the journal Frontiers in Endocrinology
ISSN:1664-2392
1664-2392
DOI:10.3389/fendo.2019.00106