The Role of
            <i>de novo</i>
            Purine Synthesis in Lymphocyte Transformation

Allison, A. C.; Hovi, Tapani; Watts, R. W. E.; Webster, A. D. B.

doi:10.1002/9780470720301.ch13

Cited by 53 publications

(25 citation statements)

References 23 publications

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“…As Mg 2+ is not lost in the process of mitochondrial ATP regeneration, no new Mg 2+ ions are required to support this form of energy production. In contrast, a cell progressing through the cell cycle utilizes glycolysis and the pentose phosphate shunt to generate substrates for addition of cell mass (reviewed in (Frauwirth and Thompson, 2004)), and in lymphocytes, rapid bursts of growth are accompanied by the largely de novo synthesis of an expanded cellular pool of ATP for apportioning between its daughters (Allison et al, 1977). As each newly synthesized ATP molecule requires a new Mg 2+ ion be imported from the extracellular milieu, closely linking Mg 2+ uptake and biosynthetic metabolism is an attractively simple mechanism to allow cells to switch between quiescent and proliferative metabolic states: in the former situation, Mg 2+ uptake is limited, switching off growth pathways and focusing cellular carbon flux on (Mg 2+ ) ATP regeneration; in contrast, in the latter situation, Mg 2+ uptake is active, switching on growth pathways and focusing cellular carbon flux on synthesis of new biomolecules, including new molecules of (Mg 2+ ) ATP.…”

Section: Discussionmentioning

confidence: 99%

TRPM7 Ion Channels Are Required for Sustained Phosphoinositide 3-Kinase Signaling in Lymphocytes

2008

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Summary Lymphocytes lacking the TRPM7 dual function ion channel/protein kinase exhibit a unique phenotype: they are unable to proliferate in regular media, but proliferate normally in media supplemented with 10–15 mM extracellular Mg2+. Here, we have analyzed the molecular mechanisms underlying this phenotype. We find that upon transition from proliferation-supporting Mg2+-supplemented media to regular media, TRPM7-deficient cells rapidly downregulate their rate of growth, resulting in a secondary arrest in proliferation. The downregulated growth rate of transitioning cells is associated with a deactivation of signaling downstream from phosphoinositide 3-kinase, and expression of constitutively active p110 phosphoinositide 3-kinase is sufficient to support growth and proliferation of TRPM7-deficient cells in regular media. Together, these observations indicate that TRPM7 channels are required for sustained phosphoinositide 3-kinase-dependent growth signaling, and therefore that TRPM7 is positioned alongside phosphoinositide 3-kinases as a central regulator of lymphocyte growth and proliferation.

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Section: Discussionmentioning

confidence: 99%

TRPM7 Ion Channels Are Required for Sustained Phosphoinositide 3-Kinase Signaling in Lymphocytes

2008

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“…Of the two IMPDH isoforms, IMPDH1 is expressed in most cell types, whereas IMPDH2 is expressed in activated lymphocytes [37]. MPA inhibits IMPDH2 up to four to five-fold more compared with IMPDH1, resulting in more potent cytostatic effects of MPA on lymphocytes than on other cells [3,35]. …”

Section: Pharmacodynamicsmentioning

confidence: 99%

PharmGKB summary

Lamba¹,

Sangkuhl²,

Sanghavi³

et al. 2014

Pharmacogenetics and Genomics

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“…Guanosine nucleotide deficiency is expected to inhibit not only proliferation of eukaryotic cells, but also the replication of DNA and RNA viruses (Markland et al 2000). In this respect, it has been shown that IMPDH inhibition has the strongest influence on both T-and B-lymphocytes because they are critically dependent on de novo synthesis, rather than using the salvage pathway for guanosines (Allison et al 1977;Allison and Eugui 2000;Takebe et al 2004). Thus, IMPDH seems to be an important clinical target, and IMPDH inhibitors have received growing interest in recent years as drugs for antiviral, antibacterial, anti-proliferative, and immunosuppressive treatments (Nair and Shu 2007;Shu and Nair 2008;Petrelli et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Ultrastructure of Cytoplasmic and Nuclear Inosine-5’-Monophosphate Dehydrogenase 2 “Rods and Rings” Inclusions

Jůda

Šmigová

Kováčik

et al. 2014

J Histochem Cytochem.

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Inosine-5′-monophosphate dehydrogenase catalyzes the critical step in the de novo synthesis of guanosine nucleotides: the oxidation of inosine monophosphate to xanthosine monophosphate. This reaction can be inhibited by specific inhibitors, such as ribavirin or mycophenolic acid, which are widely used in clinical treatment when required to inhibit the proliferation of viruses or cells. However, it was recently found that such an inhibition affects the cells, leading to a redistribution of IMPDH2 and the appearance of IMPDH2 inclusions in the cytoplasm. According to their shape, these inclusions have been termed "Rods and Rings" (R&R). In this work, we focused on the subcellular localization of IMPDH2 protein and the ultrastructure of R&R inclusions. Using microscopy and western blot analysis, we show the presence of nuclear IMPDH2 in human cells. We also show that the nuclear pool has an ability to form Rod structures after inhibition by ribavirin. Concerning the ultrastructure, we observed that R&R inclusions in cellulo correspond to the accumulation of fibrous material that is not surrounded by a biological membrane. The individual fibers are composed of regularly repeating subunits with a length of approximately 11 nm. Together, our findings describe the localization of IMPDH2 inside the nucleus of human cells as well as the ultrastructure of R&R inclusions.

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The Role of de novo Purine Synthesis in Lymphocyte Transformation

Cited by 53 publications

References 23 publications

TRPM7 Ion Channels Are Required for Sustained Phosphoinositide 3-Kinase Signaling in Lymphocytes

TRPM7 Ion Channels Are Required for Sustained Phosphoinositide 3-Kinase Signaling in Lymphocytes

PharmGKB summary

Ultrastructure of Cytoplasmic and Nuclear Inosine-5’-Monophosphate Dehydrogenase 2 “Rods and Rings” Inclusions

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