scholarly journals Dynamic metabolic network modeling of a mammalian cell cycle using time-course multi-omics data

2021 ◽  
Author(s):  
Ho-Joon Lee ◽  
Fangzhou Shen ◽  
Alec Eames ◽  
Mark P Jedrychowski ◽  
Sriram Chandrasekaran
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Time Course ◽  
Metabolic Networks ◽  
Proteomics Data ◽  
Modeling Framework ◽  
Dynamic Genome ◽  
Metabolic Network Modeling ◽  
Cell Growth And Proliferation ◽  
The Impact

Cell cycle is a fundamental process for cell growth and proliferation, and its dysregulation leads to many diseases. How metabolic networks are regulated and rewired during the cell cycle is unknown. Here we apply a dynamic genome-scale metabolic modeling framework (DFA) to simulate a cell cycle of cytokine-activated murine pro-B cells. Phase-specific reaction activity predicted by DFA using time-course metabolomics were validated using matched time-course proteomics and phospho-proteomics data. Our model correctly predicted changes in methionine metabolism at the G1/S transition and the activation of lysine metabolism, nucleotides synthesis, fatty acid elongation and heme biosynthesis at the critical G0/G1 transition into cell growth and proliferation. Metabolic fluxes predicted from proteomics and phosphoproteomics constrained metabolic models were highly consistent with DFA fluxes and revealed that most reaction fluxes are regulated indirectly. Our model can help predict the impact of changes in nutrients, enzymes, or regulators on this critical cellular process.

scholarly journals Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2643
Author(s):  
Fuguang Zhao ◽  
Olesya Vakhrusheva ◽  
Sascha D. Markowitsch ◽  
Kimberly S. Slade ◽  
Igor Tsaur ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Bladder Cancer ◽  
Cell Growth ◽  
Significant Inhibition ◽  
Cycle Arrest ◽  
Damage Repair ◽  
Autophagy Induction ◽  
Cell Growth And Proliferation ◽  
The Impact

Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit DNA damage repair, the impact of artesunate on cisplatin-resistant BCa was evaluated. Cisplatin-sensitive (parental) and cisplatin-resistant BCa cells, RT4, RT112, T24, and TCCSup, were treated with ART (1–100 µM). Cell growth, proliferation, and cell cycle phases were investigated, as were apoptosis, necrosis, ferroptosis, autophagy, metabolic activity, and protein expression. Exposure to ART induced a time- and dose-dependent significant inhibition of tumor cell growth and proliferation of parental and cisplatin-resistant BCa cells. This inhibition was accompanied by a G0/G1 phase arrest and modulation of cell cycle regulating proteins. ART induced apoptos is by enhancing DNA damage, especially in the resistant cells. ART did not induce ferroptosis, but led to a disturbance of mitochondrial respiration and ATP generation. This impairment correlated with autophagy accompanied by a decrease in LC3B-I and an increase in LC3B-II. Since ART significantly inhibits proliferative and metabolic aspects of cisplatin-sensitive and cisplatin-resistant BCa cells, it may hold potential in treating advanced and therapy-resistant BCa.

scholarly journals The Impact of Coilin Nonsynonymous SNP Variants E121K and V145I on Cell Growth and Cajal Body Formation: The First Characterization

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 895
Author(s):  
Yue Yao ◽  
Heng Wee Tan ◽  
Zhan-Ling Liang ◽  
Gao-Qi Wu ◽  
Yan-Ming Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Structure ◽  
Cell Growth ◽  
Subcellular Localization ◽  
Structure Prediction ◽  
Bioinformatic Analysis ◽  
Survival Motor Neuron ◽  
Cajal Body ◽  
Survival Motor Neuron Protein ◽  
The Impact

Coilin is the main component of Cajal body (CB), a membraneless organelle that is involved in the biogenesis of ribonucleoproteins and telomerase, cell cycle, and cell growth. The disruption of CBs is linked to neurodegenerative diseases and potentially cancers. The coilin gene (COIL) contains two nonsynonymous SNPs: rs116022828 (E121K) and rs61731978 (V145I). Here, we investigated for the first time the functional impacts of these coilin SNPs on CB formation, coilin subcellular localization, microtubule formation, cell growth, and coilin expression and protein structure. We revealed that both E121K and V145I mutants could disrupt CB formation and result in various patterns of subcellular localization with survival motor neuron protein. Noteworthy, many of the E121K cells showed nucleolar coilin accumulation. The microtubule regrowth and cell cycle assays indicated that the E121K cells appeared to be trapped in the S and G2/M phases of cell cycle, resulting in reduced cell proliferation. In silico protein structure prediction suggested that the E121K mutation caused greater destabilization on the coilin structure than the V145I mutation. Additionally, clinical bioinformatic analysis indicated that coilin expression levels could be a risk factor for cancer, depending on the cancer types and races.

scholarly journals Bombyx mori Dihydroorotate Dehydrogenase: Knockdown Inhibits Cell Growth and Proliferation via Inducing Cell Cycle Arrest

2018 ◽  
Vol 19 (9) ◽  
pp. 2581 ◽  
Author(s):  
Erhu Zhao ◽  
Xiaolan Jiang ◽  
Hongjuan Cui
Keyword(s):  
Cell Cycle ◽  
Amino Acid ◽  
Dna Replication ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Bombyx Mori ◽  
Dihydroorotate Dehydrogenase ◽  
Pyrimidine Synthesis ◽  
Cycle Arrest ◽  
Cell Growth And Proliferation

Dihydroorotate dehydrogenase (DHODH), in the de novo pyrimidine biosynthetic pathway, is the fourth enzyme of pyrimidine synthesis and is used to oxidize dihydroorotate and hence to orotat. We cloned and characterized here the dhod of silkworms, Bombyx mori. The full-length cDNA sequence of dhod is 1339 bp, including an open reading frame (ORF) of 1173 bp that encoded a 390 amino acid protein. And two domains were involved in the Dihydroorotate dehydrogenase amino acid sequence of silkworms, Bombyx mori (BmDHODH), namely a DHO_dh domain and a transmembrane domain in N-termina. The silkworm dhod is expressed throughout development and in nine tissues. Moreover, knockdown of the silkworm dhod gene reduced cell growth and proliferation through G2/M phase cell cycle arrest. Similarly, DHODH inhibitor (leflunomide) also reduced cell growth and proliferation, with a significant decrease of cyclin B and cdk2. DHODH is the fourth enzyme of pyrimidine synthesis, so we also found that leflunomide can inhibit, at least in part, the endomitotic DNA replication in silk glands cells. These findings demonstrate that downregulation of BmDHODH inhibits cell growth and proliferation in silkworm cells, and the endomitotic DNA replication in silk gland cells.

scholarly journals The sweet side of the cell cycle

2017 ◽  
Vol 45 (2) ◽  
pp. 313-322 ◽  
Author(s):  
Ee Phie Tan ◽  
Francesca E. Duncan ◽  
Chad Slawson
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Growth ◽  
Chromosomal Segregation ◽  
Cellular Environment ◽  
Mammalian Cell Cycle ◽  
Intracellular Proteins ◽  
Organismal Development ◽  
Cell Growth And Proliferation ◽  
Mitosis And Meiosis

Cell division (mitosis) and gamete production (meiosis) are fundamental requirements for normal organismal development. The mammalian cell cycle is tightly regulated by different checkpoints ensuring complete and precise chromosomal segregation and duplication. In recent years, researchers have become increasingly interested in understanding how O-GlcNAc regulates the cell cycle. The O-GlcNAc post-translation modification is an O-glycosidic bond of a single β-N-acetylglucosamine sugar to serine/threonine residues of intracellular proteins. This modification is sensitive toward changes in nutrient levels in the cellular environment making O-GlcNAc a nutrient sensor capable of influencing cell growth and proliferation. Numerous studies have established that O-GlcNAcylation is essential in regulating mitosis and meiosis, while loss of O-GlcNAcylation is lethal in growing cells. Moreover, aberrant O-GlcNAcylation is linked with cancer and chromosomal segregation errors. In this review, we will discuss how O-GlcNAc controls different aspects of the cell cycle with a particular emphasis on mitosis and meiosis.

scholarly journals Metabolic status rather than cell cycle signals control quiescence entry and exit

2011 ◽  
Vol 192 (6) ◽  
pp. 949-957 ◽  
Author(s):  
Damien Laporte ◽  
Anne Lebaudy ◽  
Annelise Sahin ◽  
Benoît Pinson ◽  
Johanna Ceschin ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Cell Growth ◽  
Carbon Source ◽  
Schizosaccharomyces Pombe ◽  
Metabolic Status ◽  
Cellular Structures ◽  
Entry And Exit ◽  
Molecular Determinants ◽  
Cell Growth And Proliferation

Quiescence is defined as a temporary arrest of proliferation, yet it likely encompasses various cellular situations. Our knowledge about this widespread cellular state remains limited. In particular, little is known about the molecular determinants that orchestrate quiescence establishment and exit. Here we show that upon carbon source exhaustion, budding yeast can enter quiescence from all cell cycle phases. Moreover, using cellular structures that are candidate markers for quiescence, we found that the first steps of quiescence exit can be triggered independently of cell growth and proliferation by the sole addition of glucose in both Saccharomyces cerevisiae and Schizosaccharomyces pombe. Importantly, glucose needs to be internalized and catabolized all the way down to glycolysis to mobilize quiescent cell specific structures, but, strikingly, ATP replenishment is apparently not the key signal. Altogether, these findings strongly suggest that quiescence entry and exit primarily rely on cellular metabolic status and can be uncoupled from the cell cycle.

The Impact of Autophagy on the Progression of the Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3163-3163
Author(s):  
Fathima Shahla Vilcassim ◽  
Ashish Banerjee ◽  
George Grigoriadis
Keyword(s):  
Cell Growth ◽  
Iron Overload ◽  
Cell Lines ◽  
Western Blotting ◽  
Iron Metabolism ◽  
Myeloid Cell ◽  
Iron Chelator ◽  
Iron Chelators ◽  
Cell Growth And Proliferation ◽  
The Impact

Abstract Introduction About 75% of myelodysplastic syndromes (MDS) are lower risk categories with a paucity of definitive treatment and only supportive management as an option. MDS, defined by ineffective erythropoiesis produces anemia requiring frequent blood transfusions resulting in systemic iron overload. Refractory Anaemia with ring sideroblasts frequently characterised by mutations in the spliceosome machinery also contributes to cellular iron overload. Excess iron drives activation of the transcription factor NF-κB promoting pro-inflammatory cytokines production supporting tumour growth. Iron chelation is routinely used to treat transfusional iron overload. A number of observational studies have demonstrated that the iron chelator Deferasirox (DFX), improves haemoglobin levels in a subset of MDS patients (Messa, et al. 2008, Banerjee, et al. 2015). Iron metabolism is deregulated in cancer cells resulting in a net iron influx enhancing ROS production. Excess ROS promotes autophagy, a catabolic cellular recycling pathway clearing redundant and damaged organelles to sustain cellular metabolism. Autophagy is initiated by the Atg1-Atg13 protein complex and can be upregulated in cancer facilitating the propagation of the malignant clone. We have previously demonstrated that treatment with the iron chelator DFX, blocked growth of myeloid leukemia cell lines whilst sparing normal stem cells. Herein, we demonstrate that the growth inhibitory effects of DFX are mediated by its ability to inhibit autophagy. We therefore postulate that modulation of intracellular iron levels can be adopted as a viable tool to further elucidate the role of autophagy in this disease. Aims To explore the impact of iron modulation on autophagy. To elucidate the role autophagy in myeloid cell growth and proliferation. Methods Thp-1 (myeloid cell line) expressing the autophagy reporter LC3-GFP was utilised. Autophagy results in LC3 recruitment to the autphagosomal membrane. These cells were treated with DFX in the presence/absence of chloroquine, a lysosomal enzyme inhibitor to visualise accumulated LC3-II. Cells were also treated with two other iron chelators, deferoxamine (DFO) and Dp44mT. Treated cells were then analysed using AMNIS Flow Imaging. Acute myeloid leukaemia cell lines were treated with DFX in the presence/absence of chloroquine and subjected to Western blotting using anti-LC3-II antibody. AML cell lines were also treated with 3-methyl adenine (3MA), an autophagy inhibitor. Doxycycline inducible CRISPR/Cas9 gene editing was used to delete essential autophagy genes, ATG 5 and 7 in Thp-1 cells and subjected to Western Blotting using ATG5/7 antibodies. Cell proliferation assays were done in the presence and absence of doxycycline. The impact of ATG5/7 deletion on LC3 was analysed using Western Blotting. Results CQ treatment of Thp-1-LC3-GFP cells demonstrated an increased number of LC3 specks, which were significantly reduced upon co-treatment with DFX. The total number of cells overall with LC3 specks was also reduced in the combination treatment of CQ and DFX. This was consistent with Western Blotting results that demonstrated lower LC3-II levels in this treatment. Cells treated with the other iron chelators, DFO and Dp44mT demonstrated no decrease in LC3 specks upon co-treatment with CQ and confirmed with Western Blotting demonstrating no change in LC3-II levels. Pharmacological inhibition of autophagy in AML cell lines using 3MA, showed dose dependent decrease in cell growth. ATG5 and ATG7 editing in Thp-1 cells using CRISPR/Cas9 resulted in significant impact on cell growth and proliferation. Loss of ATG5 and ATG7 in these cellswas confirmed using Western Blotting. LC3-II levels were significantly reduced in ATG5/7 deleted cells. Conclusion Our results demonstrate an essential role for the autophagy mediators ATG5/7 highlighting the importance of autophagy in promoting proliferation of malignant myeloid cells. The negative impact of DFX on cell growth and proliferation appears to be via its ability to inhibit autophagy. This is a unique property of DFX not observed with other iron chelators. Using DFX as a tool to modulate iron metabolism, these results have reinforced the role of deregulated iron metabolism in propagation of malignant haematopoietic cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation

2019 ◽  
Vol 18 (7) ◽  
pp. 1330-1344 ◽  
Author(s):  
Tommy Weiss-Sadan ◽  
Gal Itzhak ◽  
Farnusch Kaschani ◽  
Zhanru Yu ◽  
Mohamed Mahameed ◽  
...  
Keyword(s):  
Cell Growth ◽  
Metabolic Networks ◽  
Cathepsin L ◽  
Cell Growth And Proliferation

A characterization of the effects of Dpp signaling on cell growth and proliferation in theDrosophilawing

Development ◽  
2002 ◽  
Vol 129 (4) ◽  
pp. 1003-1013 ◽  
Author(s):  
Cristina Martín-Castellanos ◽  
Bruce A. Edgar
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Cell Cycle Progression ◽  
Ectopic Expression ◽  
Specific Inhibitor ◽  
Wing Disc ◽  
Cycle Progression ◽  
Cell Growth And Proliferation ◽  
Wing Cell

Cell proliferation and patterning must be coordinated for the development of properly proportioned organs. If the same molecules were to control both processes, such coordination would be ensured. Here we address this possibility in the Drosophila wing using the Dpp signaling pathway. Previous studies have shown that Dpp forms a gradient along the AP axis that patterns the wing, that Dpp receptors are autonomously required for wing cell proliferation, and that ectopic expression of either Dpp or an activated Dpp receptor, TkvQ253D, causes overgrowth. We extend these findings with a detailed analysis of the effects of Dpp signaling on wing cell growth and proliferation. Increasing Dpp signaling by expressing TkvQ253D accelerated wing cell growth and cell cycle progression in a coordinate and cell-autonomous manner. Conversely, autonomously inhibiting Dpp signaling using a pathway specific inhibitor, Dad, or a mutation in tkv, slowed wing cell growth and division, also in a coordinate fashion. Stimulation of cell cycle progression by TkvQ253D was blocked by the cell cycle inhibitor RBF, and required normal activity of the growth effector, PI3K. Among the known Dpp targets, vestigial was the only one tested that was required for TkvQ253D-induced growth. The growth response to altering Dpp signaling varied regionally and temporally in the wing disc, indicating that other patterned factors modify the response.

Sign in / Sign up

Export Citation Format

Share Document