Two-way communication between the metabolic and cell cycle machineries: the molecular basis.

REVIEW Cell Cycle 14:13, 2022--2032; July 1, 2015; © 2015 Taylor & Francis Group, LLC Two-way communication between the metabolic and cell cycle machineries: the molecular basis Joanna Kaplon1,y, Loes van Dam1,2,y, and Daniel Peeper1,* 1 Division of Molecular Oncology; The Netherlands Cancer Institute; Amsterdam; The Netherlands; 2Department Molecular Cancer Research; Division of Biomedical Genetics; University Medical Center Utrecht; Utrecht, The Netherlands y These authors contributed equally to this work. Keywords: cell cycle, cyclin-dependent kinases, glycolysis, metabolism, nutrients, proliferation The relationship between cellular metabolism and the cell cycle machinery is by no means unidirectional. The ability of a cell to enter the cell cycle critically depends on the availability of metabolites. Conversely, the cell cycle machinery commits to regulating metabolic networks in order to support cell survival and proliferation. In this review, we will give an account of how the cell cycle machinery and metabolism are interconnected. Acquiring information on how communication takes place among metabolic signaling networks and the cell cycle controllers is crucial to increase our understanding of the deregulation thereof in disease, including cancer. Resting cells require a basal level of catabolic metabolism to ensure energy homeostasis. Cells that commit to entering the cell cycle, however, differ greatly from resting cells in terms of their metabolic profile, as they will eventually have to double their cell content, that is, their DNA, membranes, organelles and other biomass. To support the energy-consuming processes needed for this program, cells increase the uptake of glucose and glutamine and shut down oxidative metabolism. In this way, glucose and glutamine-derived metabolic intermediates can be used for the biosynthesis of macromolecules required for the cell division. Highly proliferating cells, including cancer cells but also activated lymphocytes, thymocytes and embryonic cells, preferentially use glycolysis even in the presence of oxygen.1-8 This phenomenon is called aerobic glycolysis or “the Warburg effect”.9 In unicellular organisms, cell cycle progression is dependent on the availability of nutrients, which directly couples available resources to the generation of progeny. For example, stationaryphase yeast switches to a mitotic phenotype when exposed to glucose, but becomes quiescent or sporulates when no other nutrients are provided.10 Under nutrient-steady growth conditions, cycling yeast cells display fluctuations in oxygen consumption, alternating between glycolysis and respiration. Their cell division is solely limited to the glycolytic phase, with DNA replication taking place only during that period.11 Interestingly, many genes identified in classic screens for factors regulating the *Correspondence to: Daniel S Peeper; Email: Submitted: 02/27/2015; Accepted: 04/18/2015 http://dx.doi.org/10.1080/15384101.2015.1044172 2022 cell cycle in yeast, were later shown to have a function in metabolic regulation, too.12-17 Also, transcriptome studies demonstrated that yeast genes involved in glycolysis respiration, lipids and amino acid synthesis are expressed as a function of the cell cycle.18,19 Taken together, these observations show that in unicellular organisms, intimate connections between cell cycle and metabolism must exist. In contrast to single-cell eukaryotes, cells of multicellular organisms usually have an unlimited access to nutrients. However, they are not cell-autonomous for nutrient uptake but instead depend on proliferation-regulating pathways. Mitogen-mediated activation of signaling routes triggers nutrient uptake and represents the rate-limiting cue for cell cycle entry.20 As a consequence, growth factorstimulated cells initiate cell division in a fashion comparable to that of yeast exposed to a nutrient-rich medium.21,22 Accordingly, in the absence of mitogens, even in a nutrient-rich environment, cells will not enter the cell cycle.23 On the other hand, even in the presence of promitogenic cues, glucose deprivation will keep cells from proliferating, which is a widely used method for synchronizing mammalian cells.24 The fact that signaling pathways coordinating cell cycle progression control, and are controlled by, changes in cellular metabolism25,26 shows that, also in multicellular organisms, there must be a crosstalk between these pathways, cell cycle and metabolism. Yet, the molecular basis that connects nutrient availability, biosynthetic intermediates and energetic balance to the core cell cycle machinery remains incompletely understood. Here, we will give an overview of how the cell cycle machinery and metabolism are interconnected. Cell Cycle Regulation of Metabolism Evidence is emerging in support of the coordinated temporal regulation of metabolism directly by the cell cycle modulators. A first indication for this came from the observation that in yeast, metabolites of nucleotide, protein and lipid synthesis are cyclically fluctuating, as a function of cell cycle progression.27 Indeed, it has been shown subsequently that the glycolysis-promoting enzyme 6phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is subjected to cell cycle dependent temporal regulation by members of the ubiquitin proteasome system (UPS; Figure 1, upper panel).28,29 Since then, a number of mechanisms have been revealed that couple the cellular metabolic state to the cell cycle (Fig. 2). Cell Cycle Volume 14 Issue 13 Figure 1. Protein activities and metabolic events during the cell cycle. A schematic representation of the temporal regulation of metabolic factors (upper panel) and the cell cycle machinery (lower panel). The represented protein levels are not relative, but rather indicate their relative timing of expression. Most somatic cells are differentiated and quiescent, that is, they reside in the G0 phase of the cell cycle. Following mitogenic stimulation, cells typically re-enter the cell cycle and proceed through the G1 phase, in which the stage is set for DNA replication. Upon passage through the G1/S restriction point, cells enter S phase in which they double their DNA content, move on into the G2 phase and the final mitotic (M) phase, in which cellular contents are divided over 2 daughter cells (Fig. 2). Key proteins for the tight regulation of the cell cycle are cyclin-dependent kinases (CDKs), which associate with one of different cyclins across www.tandfonline.com the cell cycle to ensure accurate cell cycle progression.30-33 The kinase activity of cyclin-CDK complexes is tightly regulated by a plethora of CDK inhibitors (CKIs), which stop cell cycle progression in unfavorable circumstances.34 D-type cyclins The role of D-type cyclins in metabolism was first demonstrated in cyclin D-deficient mice that display marked metabolic phenotypes. Cyclin D2-deficient mice show a diabetic phenotype due to impaired p (...truncated)