Research Papers:

The tumor-associated YB-1 protein: new player in the circadian control of cell proliferation

Cristina Pagano, Orsola di Martino, Gennaro Ruggiero, Andrea Maria Guarino, Nathalie Mueller, Rima Siauciunaite, Markus Reischl, Nicholas Simon Foulkes, Daniela Vallone and Viola Calabro _

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Oncotarget. 2017; 8:6193-6205. https://doi.org/10.18632/oncotarget.14051

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Cristina Pagano1,*, Orsola di Martino2,*, Gennaro Ruggiero1, Andrea Maria Guarino2, Nathalie Mueller1, Rima Siauciunaite1, Markus Reischl3, Nicholas Simon Foulkes1, Daniela Vallone1, Viola Calabrò2

1Institute of Toxicology and Genetics (ITG) Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany

2Department of Biology, University of Naples “Federico II”, 80126 Naples, Italy

3Institute for Applied Computer Science (IAI) Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany

*Co-first authors

Correspondence to:

Daniela Vallone, email: [email protected]

Viola Calabrò, email: [email protected]

Keywords: circadian clock, cell proliferation, cell cycle, Y-box binding protein, SUMOylation

Received: May 20, 2016     Accepted: December 12, 2016     Published: December 20, 2016


Correct spatial and temporal control of cell proliferation is of fundamental importance for tissue homeostasis. Its deregulation has been associated with several pathological conditions. In common with almost every aspect of plant and animal biology, cell proliferation is dominated by day-night rhythms generated by the circadian clock. However, our understanding of the crosstalk between the core clock and cell cycle control mechanisms remains incomplete. In this study, using zebrafish as a vertebrate model system, we show that the nuclear localization of the Y-box binding protein 1 (YB-1), a regulator of cyclin expression and a hallmark of certain cancers, is robustly regulated by the circadian clock. We implicate clock-controlled changes in YB-1 SUMOylation as one of the mechanisms regulating its periodic nuclear entry at the beginning of the light phase. Furthermore, we demonstrate that YB-1 nuclear protein is able to downregulate cyclin A2 mRNA expression in zebrafish via its direct interaction with the cyclin A2 promoter. Thus, by acting as a direct target of cyclic posttranslational regulatory mechanisms, YB-1 serves as one bridge between the circadian clock and its cell cycle control.

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