Cytosolic 5′-nucleotidase hyperactivity in erythrocytes of Lesch–Nyhan syndrome patients

Pesi, Rossana; Micheli, Vanna; Jacomelli, Gabriella; Peruzzi, Luana; Camici, Marcella; Garcia‐Gil, Mercedes; Allegrini, Simone; Tozzi, Maria Grazia

doi:10.1097/00001756-200006260-00006

Cited by 51 publications

(43 citation statements)

References 7 publications

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“…These results were unexpected, because acadesine inhibits glucocorticoid-induced apoptosis in quiescent thymocytes, 16 apoptosis caused by serum deprivation in fibroblasts overproducing fructose 2,6-bisphosphate, 17 and ceramide-induced apoptosis in primary astrocytes. 18 In agreement with our results, recently it has been reported that acadesine causes apoptosis in 2 neuroblastoma cell lines 38 and a hepatoma cell line. 39 These results indicate that acadesine can either induce or inhibit apoptosis depending on the cell type.…”

Section: Discussionsupporting

confidence: 93%

Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes

Campàs

López

Santidrián

et al. 2003

Blood

127

104

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Most of the circulating cells appear to be nondividing and the clonal excess of B cells is mainly caused by defects that prevent programmed cell death rather than by alterations in cell cycle regulation. 3 Glucocorticoids and other chemotherapeutic agents used clinically, including the nucleoside analogues 2-chloro-2Ј-deoxyadenosine and fludarabine, induce apoptosis in B-CLL lymphocytes, [4][5][6][7][8] suggesting that apoptosis is the mechanism of their therapeutic action. Several signaling pathways regulate apoptosis induced by chemotherapy. Thus, we recently demonstrated that phosphatidylinositol 3-kinase and protein kinase C play important roles in the survival of B-CLL cells. Furthermore, inhibition of these kinases increases glucocorticoid-and fludarabine-induced apoptosis ex vivo in the presence of survival factors. 9 The precursor of nucleotide biosynthesis acadesine or 5-aminoimidazole-4-carboxamide (AICA) riboside has various effects in several types of eukaryotic cells. These effects include inhibition of growth and depletion of pyrimidine nucleotide pools in fibroblasts, 10,11 accelerated repletion of purine nucleotide pools in heart, 12 reduction of endurance in skeletal muscle, 13 inhibition of fatty acid, sterol synthesis, and gluconeogenesis in hepatocytes, and increase in glucose uptake in muscle. 14 Acadesine is phosphorylated to AICA ribotide (ZMP), which mimics 5Ј-adenosine monophosphate (AMP) and activates both AMP-activated protein kinase (AMPK) and AMPK kinase (AMPKK). 14,15 The effects on glucose and lipid metabolism are mediated through activation of the AMPK cascade. 14 Previous studies report that acadesine inhibits glucocorticoidinduced apoptosis in quiescent thymocytes, 16 apoptosis caused by serum deprivation in fibroblasts overproducing fructose 2,6-bisphosphate, 17 and ceramide-induced apoptosis in primary astrocytes. 18 To contribute to the understanding of glucocorticoidinduced apoptosis in B-CLL cells, we attempted to block apoptosis with acadesine and, surprisingly, we found that acadesine induced apoptosis in B-CLL cells, whereas T cells from these patients were not affected. Here we study the mechanism of acadesine-induced apoptosis and propose a new pathway involving AMPK and AMPKK in the control of apoptosis in B-CLL cells. Reprints: Joan Gil, Departament de Ciè ncies Fisiolò giques II, Campus de Bellvitge, Universitat de Barcelona, c/ Feixa Llarga s/n, E-08907 L'Hospitalet de Llobregat, Spain; e-mail: joangil@bellvitge.bvg.ub.es.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. Patients, materials, and methods Patients with B-CLL and cell isolationSeventy samples from patients with B-CLL who had not received treatment in the previous 6 months were studied. B-CLL was diagnosed according to standard clinical and laboratory criteria. Cells were obtained from the Hospital Clinic, Barcelona, Spain. Written inf...

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Section: Discussionsupporting

confidence: 93%

Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes

Campàs

López

Santidrián

et al. 2003

Blood

127

104

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“…Then the cycle is interrupted, causing IMP degradation by cN-II, and hypoxanthine accumulation. These results appear particularly relevant in light of our recent observations, showing that the Lesh Nyhan syndrome is metabolically related not only to a deficiency of HGPRT, but also to a three-to fivefold increase in cN-II [16]. At 2 mM initial PRPP concentration, the steady-state period lasted about 40 min, indicating that at both 1 and 2 mM PRPP initial concentrations, the velocity of the cycle remained unchanged ( fig.…”

Section: Resultssupporting

confidence: 63%

The purine nucleoside cycle in cell-free extracts of rat brain: evidence for the occurrence of an inosine and a guanosine cycle with distinct metabolic roles

Barsotti

Pesi

Felice

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

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The purine nucleoside cycle is a cyclic pathway composed of three cytosolic enzymes, hypoxanthine-guanine phosphoribosyltransferase, IMP-GMP specific 5'-nucleotidase, and purine-nucleoside phosphorylase. It may be considered a 'futile cycle', whose net reaction is the hydrolysis of 5-phosphoribosyl-1-pyrophosphate to inorganic pyrophosphate and ribose 1-phosphate. The availability of a highly purified preparation of cytosolic 5'-nucleotidase prompted us to reconstitute the purine nucleoside cycle. Its kinetics were strikingly similar to those observed when dialyzed extracts of rat brain were used. Thus, when the cycle is started by addition of inorganic phospate (Pi) and hypoxanthine or inosine (the 'inosine cycle'), steady-state levels of the intermediates are observed and the cycle 'turns over' as far as 5-phosphoribosyl-1-pyrophosphate is being consumed. In the presence of ATP, which acts both as an activator of IMP-GMP-specific 5'-nucleotidase and as substrate of nucleoside mono- and di-phosphokinases, no IDP and ITP are formed. The inosine cycle is further favored by the extremely low xanthine oxidase activity. Evidence is presented that ribose 1-phosphate needed to salvage pyrimidine bases in rat brain may arise, at least in part, from the 5-phosphoribosyl-1-pyrophosphate hydrolysis as catalyzed by the inosine cycle, showing that it may function as a link between purine and pyrimidine salvage. When the cycle is started by addition of Pi and guanine (the 'guanosine cycle'), xanthine and xanthosine are formed, in addition to GMP and guanosine, showing that the guanosine cycle 'turns over' in conjunction with the recycling of ribose 1-phosphate for nucleoside interconversion. In the presence of ATP, GDP and GTP are also formed, and the velocity of the cycle is drastically reduced, suggesting that it might metabolically modulate the salvage synthesis of guanyl nucleotides.

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“…2017;39 (2) rs11191580 confers schizophrenia risk Low cN-II activity was also found to be present in the brain. 17 Pesi et al 18 reported that fluctuations in cN-II activity were involved with the pathological mechanism of Lesch-Nyhan syndrome, a metabolic-neurological syndrome related to hypoxanthine phosphoribosyl transferase deficiency. Moreover, a knockdown study in human astrocytoma cells revealed that cN-II activity was essential for their survival.…”

Section: Tablementioning

confidence: 99%

The rs11191580 variant of the NT5C2 gene is associated with schizophrenia and symptom severity in a South Chinese Han population: evidence from GWAS

Li¹,

Jiang

Long

et al. 2016

Rev. Bras. Psiquiatr.

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Objective: Recent genome-wide association studies have identified a significant relationship between the NT5C2 variant rs11191580 and schizophrenia (SCZ) in European populations. This study aimed to validate the association of rs11191580 polymorphism with SCZ risk in a South Chinese Han population. The relationship of this polymorphism with the severity of SCZ clinical symptoms was also explored. Methods: A case-control study was performed in 462 patients with SCZ and 598 healthy controls. rs11191580 was genotyped by the Sequenom MassARRAY iPLEX platform. A total of 459 SCZ patients completed the Positive and Negative Syndrome Scale (PANSS) evaluation. Data were analyzed by PLINK software. Results: We confirmed an association of the rs11191580 polymorphism with SCZ risk in South Chinese Han under a dominant genetic model (OR adj = 0.769; 95%CI adj = 0.600-0.984; p adj = 0.037). PANSS scores showed a significant association between variant rs11191580 and total score (p adj = 0.032), lack of response scale score (p adj = 0.022), and negative scale score (additive: p adj = 0.004; dominant: p adj = 0.016; recessive: p adj = 0.021) after data were adjusted for age and sex. Conclusion: NT5C2 variant rs11191580 conferred susceptibility to SCZ and affected the clinical symptoms of SCZ in a South Chinese Han population.

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Cytosolic 5′-nucleotidase hyperactivity in erythrocytes of Lesch–Nyhan syndrome patients

Cited by 51 publications

References 7 publications

Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes

Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes

The purine nucleoside cycle in cell-free extracts of rat brain: evidence for the occurrence of an inosine and a guanosine cycle with distinct metabolic roles

The rs11191580 variant of the NT5C2 gene is associated with schizophrenia and symptom severity in a South Chinese Han population: evidence from GWAS

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