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

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.

Dephosphorylation of YB-1 is Required for Nuclear Localisation During G2 Phase of the Cell Cycle

“…Our finding that the cellular location of YB-1 is cell cycle dependent is in line with earlier reports [14,15,21,[40][41][42]. YB-1 has been shown to transcriptionally activate mRNAs for the cyclins CCNA1 and CCNB1 [14] as well as CDC6 [40].…”

“…These findings are in line with our finding that YB-1 moves into the nucleus during the G 2 /M transition, potentially to bind with mRNAs identified by Kotake et al [15]. In line with this, nuclear YB-1 has been shown to interact directly with the cyclin A2 promoter leading to a downregulation of cyclin A2 mRNA expression in zebrafish [42]. In addition to this transcriptional role, YB-1 may also play a post-translational regulatory role.…”

“…In addition to this transcriptional role, YB-1 may also play a post-translational regulatory role. These same authors demonstrate that presence of YB-1 in the nucleus is driven by a circadian clock mechanism and involves the SUMOylation of YB-1 [42]. YB-1 has been shown to be 'nuclear' in 5% of exponentially growing HeLa cells, 6-8 hours following release from lovastatin-induced G 1 arrest [14].…”

Oxidative Stress Causes Enhanced Secretion of YB-1 Protein that Restrains Proliferation of Receiving Cells

“…The expression construct 5xMyc-YB-1 was previously described [ 32 ]. Plasmid pcDNA 3.1B, used as a control, was purchased by Thermo-Fisher Scientific (Waltham, MA, USA).…”

Investigation of function and regulation of the YB-1 cellular factor in HIV replication

“…It is known that YB-1 has one nuclear export signal (NES; 52–101), three nuclear localization signals (NLS; 149–156, 185–194, 276–292), and one retention signal (CRS; 247–267), regulating the localization of YB-1 ( 18 ). Most of the YB-1 is located in the cytoplasm ( 10 , 19 ), but it can shuttle between the nucleus and the cytoplasm. YB-1 129–324 has three NLSs, localizing it in the nucleus ( 18 , 20 ).…”