Glucose restriction induces transient G2 cell cycle arrest extending cellular chronological lifespan.

Fumie Masuda,Mitsuhiro Yanagida,Kojiro Takeda,Ayaka Mori,Lisa Uehara,Mahiro Ishii,Shigeaki Saitoh

doi:10.1038/srep19629

Abstract

While glucose is the fundamental source of energy in most eukaryotes, it is not always abundantly available in natural environments, including within the human body. Eukaryotic cells are therefore thought to possess adaptive mechanisms to survive glucose-limited conditions, which remain unclear. Here, we report a novel mechanism regulating cell cycle progression in response to abrupt changes in extracellular glucose concentration. Upon reduction of glucose in the medium, wild-type fission yeast cells undergo transient arrest specifically at G2 phase. This cell cycle arrest is dependent on the Wee1 tyrosine kinase inhibiting the key cell cycle regulator, CDK1/Cdc2. Mutant cells lacking Wee1 are not arrested at G2 upon glucose limitation and lose viability faster than the wild-type cells under glucose-depleted quiescent conditions, suggesting that this cell cycle arrest is required for extension of chronological lifespan. Our findings indicate the presence of a novel cell cycle checkpoint monitoring glucose availability, which may be a good molecular target for cancer therapy.

Highlights

The target of rapamycin (TOR) kinases, which form two distinct complexes, TORC1 and TORC2, are suggested to play a pivotal role in cellular response to extracellular nutrients, such as amino acids[9,10,11,12,13]
To gain mechanistic insight into cell division control in response to limitation of extracellular glucose, we monitored cell cycle progression in WT cells transferred from high-glucose to low-glucose medium by measuring the proportion of cells with a septum, which is a useful hallmark of cytokinesis (Fig. 1A)
The length of cells did not increase after the shift to low-glucose medium, but rather became shorter, suggesting that cell growth was inhibited during this arrest caused by glucose restriction, unlike cell cycle arrest due to stresses causing DNA damage and/or incomplete DNA replication, even in the presence of which the WT cells continued to grow[41,42]

Summary

Introduction

The TOR kinases, which form two distinct complexes, TORC1 and TORC2, are suggested to play a pivotal role in cellular response to extracellular nutrients, such as amino acids[9,10,11,12,13]. When S. pombe cells are transferred from high-glucose (111 mM) medium to low-glucose (4.4 mM) medium, they stop dividing transiently before resuming rapid proliferation[26,28] Genotoxic stresses, such as DNA damage and incomplete replication, activate the checkpoint, which prevents cell cycle progression until the stresses are removed[37,38,39] In response to these genotoxic stresses, the evolutionarily conserved DNA structure checkpoint signalling cascade, upstream of which ATM (Ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) kinases act, inhibit Cdc[25], so that the cells are arrested in G2 phase. We explore the mechanism underlying the regulation of cell cycle progression under low glucose conditions, and show that glucose restriction causes transient G2 arrest in a manner dependent on Wee[1] kinase. Our findings indicate that Wee1-dependent G2 arrest is a novel checkpoint control in response to glucose restriction, which extends the chronological lifespan under conditions of glucose depletion

Methods

Results

Conclusion