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

Cristina Pagano,Nathalie Mueller,Orsola Di Martino,Nicholas Simon Foulkes,Rima Siauciunaite,Markus Reischl,Daniela Vallone,Gennaro Ruggiero,Viola Calabrò,Andrea Maria Guarino

doi:10.18632/oncotarget.14051

Cristina Pagano, Nathalie Mueller + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.14051

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Abstract

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.

Highlights

The circadian clock generates day-night rhythms in most aspects of physiology and behaviour [1]
We have previously shown that the transcription of cell cycle control genes, including zfcyclin A2 and zfcyclin B1, is regulated by the circadian clock in the adult zebrafish caudal fin [16]
Given the central role played by Y-box binding protein 1 (YB-1) in the control of the cell cycle, we wished to investigate its involvement in circadian clock-regulated cell proliferation in zebrafish

Summary

Introduction

The circadian clock generates day-night rhythms in most aspects of physiology and behaviour [1]. Central to the circadian timing system is a pacemaker that oscillates with a period of circa 24 hours and is reset on a daily basis by environmental signals such as light, food or temperature, via input pathways. The master clock regulates physiology and behaviour via clock output pathways [1, 2]. At the core of the circadian clock mechanism is a transcription-translation feedback loop, which requires approximately 24 hours to complete one cycle. The transcription factors CLOCK and BMAL activate expression of Period (Per) and Cryptochrome (Cry) genes, via binding to E-box enhancers in their promoters. Cyclic post translational modifications, protein turnover and changes in the sub-cellular localization of key clock components all combine to reinforce the core clock mechanism’s timing function [5,6,7]

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