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

Kaplon, Joanna; Dam, Loes van; Peeper, Daniel S.

doi:10.1080/15384101.2015.1044172

Cited by 84 publications

(68 citation statements)

References 151 publications

(111 reference statements)

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“…We showed that treatment of HeLa cells with the PDK inhibitor DCA eliminates the oscillations in glucose flux into TCA cycle, suggesting that cell cycle‐specific regulation of PDH activity may be involved in regulating these flux oscillations. Consistently, PDK4 was reported to be induced by the E2F‐pRB pathway which controls cell entry to S phase (Hsieh et al , ; Kaplon et al , ). Furthermore, analyzing published phosphoproteomics data for HeLa cells measured throughout the cell cycle (Olsen et al , ) shows more than twofold increase in the phosphorylation of the PDH E1 component in early and late S phase versus in G1 (Appendix Fig S18).…”

Section: Discussionmentioning

confidence: 73%

Temporal fluxomics reveals oscillations in TCA cycle flux throughout the mammalian cell cycle

Ahn

Kumar

Mukha

et al. 2017

Molecular Systems Biology

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Cellular metabolic demands change throughout the cell cycle. Nevertheless, a characterization of how metabolic fluxes adapt to the changing demands throughout the cell cycle is lacking. Here, we developed a temporal-fluxomics approach to derive a comprehensive and quantitative view of alterations in metabolic fluxes throughout the mammalian cell cycle. This is achieved by combining pulse-chase LC-MS-based isotope tracing in synchronized cell populations with computational deconvolution and metabolic flux modeling. We find that TCA cycle fluxes are rewired as cells progress through the cell cycle with complementary oscillations of glucose versus glutamine-derived fluxes: Oxidation of glucosederived flux peaks in late G1 phase, while oxidative and reductive glutamine metabolism dominates S phase. These complementary flux oscillations maintain a constant production rate of reducing equivalents and oxidative phosphorylation flux throughout the cell cycle. The shift from glucose to glutamine oxidation in S phase plays an important role in cell cycle progression and cell proliferation.

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Section: Discussionmentioning

confidence: 73%

Temporal fluxomics reveals oscillations in TCA cycle flux throughout the mammalian cell cycle

Ahn

Kumar

Mukha

et al. 2017

Molecular Systems Biology

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“…CDK inhibitors are involved in many cellular processes, including cell cycle control, transcription, cell migration and metabolism; and they can affect cell quiescence, senescence, differentiation or cell death, depending on the cellular setting 112, 143, 155, 161–164 . In most cases, these functions are mediated by inhibition of specific cyclin–CDK complexes.…”

Section: Control Of Cell Differentiationmentioning

confidence: 99%

“…Further observations that cyclin D1 can directly bind additional lipogenic enzymes and mitochondrial proteins 48 point to cyclin D1 as an important regulator of metabolic activities through different pathways 143 . In addition to cyclin D1, also cyclin E has been proposed to inhibit mitochondrial biogenesis and oxidative metabolism in a transcriptional manner, but the exact mechanism is unknown 144 .…”

Section: Roles Of Cyclins and Cdks In Metabolismmentioning

confidence: 99%

Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases

Hydbring

Malumbres

Siciński

2016

Nat Rev Mol Cell Biol

432

365

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The role of cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs), as core components of the machinery that drives cell cycle progression is well established. Increasing evidence indicates that mammalian cyclins and CDKs also carry out important roles in other cellular processes such as transcription, DNA damage repair, the control of cell death, differentiation, the immune response and metabolism. Some of these non-canonical functions are performed by cyclins or by CDKs, independent of their respective cell cycle partners, suggesting a substantial divergence in the function of these proteins during evolution.

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“…9 Furthermore, there is growing evidence supporting the role of cell cycle regulators such as cyclins and cyclin-dependent kinases in the regulation of metabolism. 10 Vpr is known to induce cell cycle arrest in G 2 /M phase. 11,12 Vpr-mediated pathogenesis in macrophages has been extensively investigated, [13][14][15] but its effects on the global molecular mechanism associated with metabolic pathways have not been characterized.…”

Section: Introductionmentioning

confidence: 99%

Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

et al. 2016

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HIV-1 infected macrophages play a significant role in the neuropathogenesis of AIDS. HIV-1 viral protein R (Vpr) not only facilitates HIV-1 infection but also contribute to long-lived persistence in macrophages. Our previous studies using SILAC-based proteomic analysis showed that the expression of critical metabolic enzymes in the glycolytic pathway and tricarboxylic acid (TCA) cycle were altered in response to Vpr expression in macrophages. We hypothesized that Vpr-induced modulation of glycolysis and TCA cycle regulates glutamate metabolism and release in HIV-1 infected macrophages.We assessed the amount of specific metabolites induced by Vpr and HIV-1 in macrophages at the intracellular and extracellular level in a time-dependent manner utilizing multiple reaction monitoring (MRM) targeted metabolomics. In addition, stable isotope-labeled glucose and an MRM targeted metabolomics assay were used to evaluate the de novo synthesis and release of glutamate in Vpr overexpressing macrophages and HIV-1 infected macrophages, throughout the metabolic flux of glycolytic pathway and TCA cycle activation.The metabolic flux studies demonstrated an increase in glucose uptake, glutamate release and accumulation of a-ketoglutarate (a-KG) and glutamine in the extracellular milieu in Vpr expressing and HIV-1 infected macrophages. Interestingly, glutamate pools and other intracellular intermediates (glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), citrate, malate, a-KG, and glutamine) showed a decreased trend except for fumarate, in contrast to the glutamine accumulation observed in the extracellular space in Vpr overexpressing macrophages.Our studies demonstrate that dysregulation of mitochondrial glutamate metabolism induced by Vpr in HIV-1 infected macrophages commonly seen, may contribute to neurodegeneration via excitotoxic mechanisms in the context of NeuroAIDS.

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

Cited by 84 publications

References 151 publications

Temporal fluxomics reveals oscillations in TCA cycle flux throughout the mammalian cell cycle

Temporal fluxomics reveals oscillations in TCA cycle flux throughout the mammalian cell cycle

Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases

Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

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