Cell cycle-dependent regulation of cellular ATP concentration, and depolymerization of the interphase microtubular network induced by elevated cellular ATP concentration in whole fibroblasts

Marcussen, Mads; Larsen, Philip J.

doi:10.1002/(sici)1097-0169(1996)35:2<94::aid-cm2>3.0.co;2-i

Cited by 42 publications

(27 citation statements)

References 25 publications

(4 reference statements)

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“…Early studies suggested that microtubules may act as a sensor of the energy state of the cell (129) with ATP depletion causing instability of detyrosinated microtubule plus ends (130, 131). AMPK is a major sensor for the metabolic state of the cell and affects microtubule dynamics by phosphorylation of CLIP170 (132).…”

Section: Microtubule Cytoskeleton In Stress Responsesmentioning

confidence: 99%

Microtubules and Their Role in Cellular Stress in Cancer

2014

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Microtubules are highly dynamic structures, which consist of α- and β-tubulin heterodimers, and are involved in cell movement, intracellular trafficking, and mitosis. In the context of cancer, the tubulin family of proteins is recognized as the target of the tubulin-binding chemotherapeutics, which suppress the dynamics of the mitotic spindle to cause mitotic arrest and cell death. Importantly, changes in microtubule stability and the expression of different tubulin isotypes as well as altered post-translational modifications have been reported for a range of cancers. These changes have been correlated with poor prognosis and chemotherapy resistance in solid and hematological cancers. However, the mechanisms underlying these observations have remained poorly understood. Emerging evidence suggests that tubulins and microtubule-associated proteins may play a role in a range of cellular stress responses, thus conferring survival advantage to cancer cells. This review will focus on the importance of the microtubule–protein network in regulating critical cellular processes in response to stress. Understanding the role of microtubules in this context may offer novel therapeutic approaches for the treatment of cancer.

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Section: Microtubule Cytoskeleton In Stress Responsesmentioning

confidence: 99%

Microtubules and Their Role in Cellular Stress in Cancer

2014

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“…These differences indicate a higher energy charge (24) in SG2M phase cells, suggesting that energy metabolism oscillates over the cell cycle. Oscillation in ATP level was previously reported in synchronized mouse 3T3 fibroblasts (25), and less pronounced oscillation in GTP level in HL-60 cells (26) and in yeast (27), suggesting that the phenomenon is deeply conserved. The nucleoside diphosphokinase enzyme (NDP kinase, encoded by NME1-9 in humans), which synthesizes NTPs from NDPs, was also found to continuously increase in activity during the cell cycle of fission yeast, with highest peak in S phase (28), possibly explaining the simultaneous increase in phosphorylation state of all nucleotides.…”

Section: Oscillating and Housekeeping Central Metabolism In Cycling Cmentioning

confidence: 62%

Mapping metabolic oscillations during cell cycle progression

Roçi

Watrous

Lagerborg

et al. 2020

Preprint

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Proliferating cells must synthesize a wide variety of macromolecules while progressing through the cell cycle, but the coordination between cell cycle progression and cellular metabolism is still poorly understood. To identify metabolic processes that oscillate over the cell cycle, we performed comprehensive, non-targeted liquid chromatography-high resolution mass spectrometry (LC-HRMS) based metabolomics of HeLa cells isolated in the G1 and SG2M cell cycle phases, capturing thousands of diverse metabolite ions. When accounting for increased total metabolite abundance due to cell growth throughout the cell cycle, 18% of the observed LC-HRMS peaks were at least 2-fold different between the stages, consistent with broad metabolic remodeling throughout the cell cycle. While most amino acids, phospholipids, and total ribonucleotides were constant across cell cycle phases, consistent with the view that total macromolecule synthesis does not vary across the cell cycle, certain metabolites were oscillating. For example, ribonucleotides were highly phosphorylated in SG2M, indicating an increase in energy charge, and several phosphatidylinositols were more abundant in G1, possibly indicating altered membrane lipid signaling. Within carbohydrate metabolism, pentose phosphates and methylglyoxal metabolites were associated with the cycle. Interestingly, hundreds of yet uncharacterized metabolites similarly oscillated between cell cycle phases, suggesting previously unknown metabolic activities that may be synchronized with cell cycle progression, providing an important resource for future studies.

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“…2 to generate two daughter cells. Marcussen and Larsen (1996) indicated that the cellular ATP concentration varies through the cell cycle, reaching a peak at G2/M phase and minimum at late G1/early S-phase. Recently, Chan et al (2013) reported that low concentrations of drugs that arrest the cell cycle at S phase or G2/M phase, induced repairable DNA damage, increase in cell size and amount of ATP per cell.…”

Section: Discussionmentioning

confidence: 99%

Chemically induced strong cellular hypertrophy often reduces the accuracy of cytotoxicity measurements obtained using the ATP assay

et al. 2017

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-The ATP assay is a highly sensitive and versatile method for measuring cytotoxicity. However, the correlation between the cell viability results obtained using the ATP assay and those obtained using direct cell counting has not been widely reported. Therefore, to evaluate the reliability and limitations of the ATP assay, we compared the results of ATP assay with those of automatic cell counter, which can measure the number and diameter of cells directly, by using 24 compounds and repeating individual experiments thrice. The correlation between the data was low for 7 of the 24 compounds (r 2 < 0.8, at least 2 out of 3 experiments). These were the top 7 of the 11 compounds that induced cell hypertrophy. These 7 compounds were also observed to increase the area of mitochondria. However, the last 4 of the 11 compounds increased the cell size but did not increase the mitochondrial area. For the remaining 13 compounds, which had no effect on cell size, a good correlation was observed between the results of the two methods (r 2 > 0.8, at least 2 out of 3 experiments), and the cell size was effectively the same as that of the controls. We concluded that the poor correlation between the two methods was attributable to an increase in the content of intracellular ATP because of the chemically induced cell and mitochondrial hypertrophy. We showed that the ATP assay is unsuitable for assessing the cytotoxicity of compounds that induce cell hypertrophy with increase in the mitochondrial area and ATP content.

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Cell cycle-dependent regulation of cellular ATP concentration, and depolymerization of the interphase microtubular network induced by elevated cellular ATP concentration in whole fibroblasts

Cited by 42 publications

References 25 publications

Microtubules and Their Role in Cellular Stress in Cancer

Microtubules and Their Role in Cellular Stress in Cancer

Mapping metabolic oscillations during cell cycle progression

Chemically induced strong cellular hypertrophy often reduces the accuracy of cytotoxicity measurements obtained using the ATP assay

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