Inhibition of T lymphocyte activation in mice heterozygous for loss of the IMPDH II gene

Gu, Jie; Stegmann, Alexander P.A.; Gathy, Karen; Murray, Robert; Laliberté, Josée; Ayscue, Lanier H.; Mitchell, Beverly S.

doi:10.1172/jci8669

Cited by 63 publications

(68 citation statements)

References 29 publications

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“…Inhibitors of IMPDH, which catalyzes the conversion of IMP into XMP during de novo GMP synthesis, could block lymphocyte proliferation leading to immunosuppression (Sollinger et al 1992;Eugui and Allison 1993). Consistently, it has been shown that the proliferation of lymphocytes could be significantly suppressed when the genes encoding for IMPDH were disrupted in mice (Gu et al 2000(Gu et al , 2003. Surprisingly, no defect in cell proliferation was observed in bur and ras mutants.…”

Section: Discussionmentioning

confidence: 85%

“…Energetically, the salvage pathway appears to be much less costly than de novo synthesis and is generally believed to be the principal pathway for the supply of guanine nucleotides in animals. While the de novo synthesis of guanine nucleotides has been shown to play a role in the proliferation of leukocytes (Eugui et al 1991;Dayton et al 1992;Hauser and Sterzel 1999;Gu et al 2000Gu et al , 2003, it is unknown if de novo synthesis is essential for any other biological processes when the food supply is sufficient. In this study, we show that the de novo synthesis of guanine nucleotides is specifically required for the pathfinding of photoreceptor (R cell) axons in the developing Drosophila visual system.…”

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confidence: 99%

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De Novo GMP Synthesis Is Required for Axon Guidance in Drosophila

Hong

Cameron

et al. 2006

Genetics

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Guanine nucleotides are key players in mediating growth-cone signaling during neural development. The supply of cellular guanine nucleotides in animals can be achieved via the de novo synthesis and salvage pathways. The de novo synthesis of guanine nucleotides is required for lymphocyte proliferation in animals. Whether the de novo synthesis pathway is essential for any other cellular processes, however, remains unknown. In a search for genes required for the establishment of neuronal connectivity in the fly visual system, we identify the burgundy (bur) gene as an essential player in photoreceptor axon guidance. The bur gene encodes the only GMP synthetase in Drosophila that catalyzes the final reaction of de novo GMP synthesis. Loss of bur causes severe defects in axonal fasciculation, retinotopy, and growth-cone morphology, but does not affect photoreceptor differentiation or retinal patterning. Similar defects were observed when the raspberry (ras) gene, encoding for inosine monophosphate dehydrogenase catalyzing the IMP-to-XMP conversion in GMP de novo synthesis, was mutated. Our study thus provides the first in vivo evidence to support an essential and specific role for de novo synthesis of guanine nucleotides in axon guidance.

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Section: Discussionmentioning

confidence: 85%

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confidence: 99%

De Novo GMP Synthesis Is Required for Axon Guidance in Drosophila

Hong

Cameron

et al. 2006

Genetics

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“…3; Table 2F). This enzyme appears to be essential to normal cell proliferation and T lymphocyte activation (Gu et al, 2000).…”

Section: Oesophagus and Stomach Expressionmentioning

confidence: 99%

Xenopus cDNA microarray identification of genes with endodermal organ expression

Park

Hayata

Cho

et al. 2007

Developmental Dynamics

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The endoderm is classically defined as the innermost layer of three Metazoan germ layers. During organogenesis, the endoderm gives rise to the digestive and respiratory tracts as well as associated organs such as the liver, pancreas, and lung. At present, however, how the endoderm forms the variety of cell types of digestive and respiratory tracts as well as the budding organs is not well understood. In order to investigate the molecular basis and mechanism of organogenesis and to identify the endodermal organ-related marker genes, we carried out microarray analysis using Xenopus cDNA chips. To achieve this goal, we isolated the Xenopus gut endoderm from three different stages of Xenopus organogenesis, and separated each stage of gut endoderm into anterior and posterior regions. Competitive hybridization of cDNA between the anterior and posterior endoderm regions, to screen genes that specifically expressed in the major organs, revealed 915 candidates. We then selected 104 clones for in situ hybridization analysis. Here, we report the identification and expression patterns of the 104 Xenopus endodermal genes, which would serve as useful markers for studying endodermal organ development.

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“…In particular, two enzymes, the inosine monophosphate dehydrogenase (IMPDH) 3 which catalyzes the first step in the formation of guanine ribonucleotides from inosine monophosphate and the thymidylate synthase (TS) which catalyzes the synthesis of deoxy-thymidine 5Ј-monophosphate from deoxy-uridine 5Ј-monophosphate, both increase 10-fold 48 h after activation of T lymphocytes (4,5). Mice heterozygous for loss of the IMPDH type II demonstrate a significant decrease of lymphocyte responsiveness to stimulation with anti-CD3 and anti-CD28 Abs, suggesting that guanine nucleotides synthesized by IMPDH type II are necessary for the proliferation of T lymphocytes (6). One may indeed speculate that clonal expansion of naive T cells depends on the activation of gene transcription involved in the stimulation of de novo purine and pyrimidine synthesis pathways (3) to provide the additional nucleotide precursors necessary for DNA synthesis.…”

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confidence: 99%

Differential Control of Cell Cycle, Proliferation, and Survival of Primary T Lymphocytes by Purine and Pyrimidine Nucleotides

Quéméneur

Gerland

Flacher

et al. 2003

The Journal of Immunology

210

166

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Purine and pyrimidine nucleotides play critical roles in DNA and RNA synthesis as well as in membrane lipid biosynthesis and protein glycosylation. They are necessary for the development and survival of mature T lymphocytes. Activation of T lymphocytes is associated with an increase of purine and pyrimidine pools. However, the question of how purine vs pyrimidine nucleotides regulate proliferation, cell cycle, and survival of primary T lymphocytes following activation has not yet been specifically addressed. This was investigated in the present study by using well-known purine (mycophenolic acid, 6-mercaptopurine) and pyrimidine (methotrexate, 5-fluorouracil) inhibitors, which are used in neoplastic diseases or as immunosuppressive agents. The effect of these inhibitors was analyzed according to their time of addition with respect to the initiation of mitogenic activation. We showed that synthesis of both purine and pyrimidine nucleotides is required for T cell proliferation. However, purine and pyrimidine nucleotides differentially regulate the cell cycle since purines control both G1 to S phase transition and progression through the S phase, whereas pyrimidines only control progression from early to intermediate S phase. Furthermore, inhibition of pyrimidine synthesis induces apoptosis whatever the time of inhibitor addition whereas inhibition of purine nucleotides induces apoptosis only when applied to already cycling T cells, suggesting that both purine and pyrimidine nucleotides are required for survival of cells committed into S phase. These findings reveal a hitherto unknown role of purine and pyrimidine de novo synthesis in regulating cell cycle progression and maintaining survival of activated T lymphocytes.

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Inhibition of T lymphocyte activation in mice heterozygous for loss of the IMPDH II gene

Cited by 63 publications

References 29 publications

De Novo GMP Synthesis Is Required for Axon Guidance in Drosophila

De Novo GMP Synthesis Is Required for Axon Guidance in Drosophila

Xenopus cDNA microarray identification of genes with endodermal organ expression

Differential Control of Cell Cycle, Proliferation, and Survival of Primary T Lymphocytes by Purine and Pyrimidine Nucleotides

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