Characterisation of inosine monophosphate dehydrogenase expression during retinal development: Differences between variants and isoforms

Gunter, Jennifer H.; Thomas, Elaine; Lengefeld, Nadia; Krüger, Sarah; Worton, Leah E.; Gardiner, Edith M.; Jones, Alun; Barnett, Nigel L.; Whitehead, Jonathan P.

doi:10.1016/j.biocel.2007.12.018

Cited by 59 publications

(80 citation statements)

References 28 publications

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“…5, a-f). In addition, IMPDH formed a filament structure under starvation conditions, which has been previously reported by other groups (27,28). We found that purinosome bodies and filament structures are different phenomena, and they are not colocalized with each other inside the cytoplasm (Fig.…”

Section: Downstream De Novo Biosynthesis Enzymes Adss and Impdh Co-supporting

confidence: 85%

Quantitative Analysis of Purine Nucleotides Indicates That Purinosomes Increase de Novo Purine Biosynthesis

Zhao

Chiaro

Zhang

et al. 2015

Journal of Biological Chemistry

110

126

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Section: Downstream De Novo Biosynthesis Enzymes Adss and Impdh Co-supporting

confidence: 85%

Quantitative Analysis of Purine Nucleotides Indicates That Purinosomes Increase de Novo Purine Biosynthesis

Zhao

Chiaro

Zhang

et al. 2015

Journal of Biological Chemistry

110

126

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“…Immunocytochemical and biochemical studies have revealed that, after treatment with inhibitors, the IMPDH enzyme, which is normally diffusely distributed throughout the cytoplasm, is reorganized into cytoplasmic inclusion bodies (Gunter et al 2008;Carcamo et al 2011;Thomas et al 2012). IMPDH inclusions, for instance, have been named "Rods and Rings" (R&R) according to their apparent shape (Dellavance et al 2009;Seelig et al 2011).…”

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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“…An emerging theme in RR research is that drugs that throttle GMP biosynthesis, either by directly inhibiting IMPDH (with mycophenolic acid or ribavirin) or indirectly by limiting essential precursor availability (by inhibiting glutamine synthetase with DON or methionine sulfoximine) likewise promote RR assembly (Calise et al, 2014b;Carcamo et al, 2011;Gou et al, 2014;Gunter et al, 2008;Ji et al, 2006). We demonstrated here that RR formation also occurs when cells are treated with methotrexate or aminopterin, which target dihydrofolate reductase.…”

Section: Discussionmentioning

confidence: 79%

“…His discovery that inosine 5′-monophosphate dehydrogenase (IMPDH, for which there are two variants, IMPDH1 and IMPDH2, in mammals), which catalyzes the reaction IMP+H 2 O+NAD + ⇌XMP+NADH+H + and is the rate-limiting enzyme in guanosine monophosphate (GMP) synthesis, is amplified in tumors and rapidly proliferating tissues (Jackson et al, 1975) was an impetus for the development of effective anticancer, immunosuppressive and antiviral chemotherapies (Chen and Pankiewicz, 2007;Nair and Shu, 2007;Ratcliffe, 2006;Shu and Nair, 2008). Later studies showed that, when cells are treated with IMPDH inhibitors or when they are deprived of nutrients required for GMP synthesis, many cells form distinctive structures termed 'rods and rings' (RRs), mainly within the cytoplasm (Calise et al, 2014b;Carcamo et al, 2011;Gunter et al, 2008;Ji et al, 2006;Thomas et al, 2012). These macromolecular assemblies take the shape of rods that are typically 3-10 µm in length or rings that most often are 2-5 µm in diameter.…”

Section: Introductionmentioning

confidence: 99%

“…In this respect, RR structures can be effectively induced in any mammalian cell line tested to date by IMPDH inhibitors (mycophenolic acid or ribavirin) or by glutaminase inhibitors or acivicin] Chen et al, 2011;Ji et al, 2006). The glutamine analog azaserine also promotes RR or cytoophidium assembly in both human and Drosophila cells (Chen et al, 2011), as do the anti-folate pemetrexed (Carcamo et al, 2014), nucleoside analog decoyinine (Gunter et al, 2008), and the uridine analog deazauridine in mammalian cells (Chang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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‘Rod and ring’ formation from IMP dehydrogenase is regulated through the one-carbon metabolic pathway

Calise

Purich

Nguyen

et al. 2016

Journal of Cell Science

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ABSTRACT'Rods and rings' (RRs) are conserved, non-membrane-bound intracellular polymeric structures composed, in part, of inosine monophosphate dehydrogenase (IMPDH), a key enzyme leading to GMP and GTP biosynthesis. RR formation is induced by IMPDH inhibitors as well as glutamine deprivation. They also form upon treatment of cells with glutamine synthetase inhibitors. We now report that depriving cells of serine and glycine promotes RR formation, and we have traced these effects to dihydrofolate reductase (DHFR) and serine hydroxymethyltransferase-2 (SHMT2), pivotal enzymes in one-carbon metabolism and nucleotide biosynthesis. RR assembly is likewise induced upon DHFR inhibition by methotrexate or aminopterin as well as siRNA-mediated knockdown of DHFR or SHMT2. Because RR assembly occurs when guanine nucleotide biosynthesis is inhibited, and because RRs rapidly disassemble after the addition of guanine nucleotide precursors, RR formation might be an adaptive homeostatic mechanism, allowing IMPDH to sense changes in the one-carbon folate pathway.

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Characterisation of inosine monophosphate dehydrogenase expression during retinal development: Differences between variants and isoforms

Cited by 59 publications

References 28 publications

Quantitative Analysis of Purine Nucleotides Indicates That Purinosomes Increase de Novo Purine Biosynthesis

Quantitative Analysis of Purine Nucleotides Indicates That Purinosomes Increase de Novo Purine Biosynthesis

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

‘Rod and ring’ formation from IMP dehydrogenase is regulated through the one-carbon metabolic pathway

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