Expression of IMPDH1 is regulated in response to mycophenolate concentration

Bremer, Sara; Vethe, Nils Tore; Rootwelt, Helge; Bergan, Stein

doi:10.1016/j.intimp.2008.10.017

Cited by 15 publications

(11 citation statements)

References 31 publications

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“…First, IMP is converted into XMP by the IMP dehydrogenase (Impdh) (Hyle et al 2003) and second, the GMP-synthase Gua1 mediates the amination of XMP to GMP (Dujardin et al 1994). Transcription of the IMD genes is strongly repressed by guanine, but activated by treatment with the Impdh inhibitors 6AU or mycophenolate (MPA) (Exinger and Lacroute 1992;Bremer et al 2009). Partial guanine deprivation results in a drastic reduction of the internal GTP pool in a yeast gua1 mutant, inducing meiosis and sporulation in homothallic strains (Varma et al 1985) and leads to concomitant reductions of the methionine and S-adenosyl-methionine (SAM) pools (Freese et al 1984).…”

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confidence: 99%

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

et al. 2011

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Purine nucleotides are structural components of the genetic material, function as phosphate donors, participate in cellular signaling, are cofactors in enzymatic reactions, and constitute the main carriers of cellular energy. Thus, imbalances in A/G nucleotide biosynthesis affect nearly the whole cellular metabolism and must be tightly regulated. We have identified a substitution mutation (G388D) that reduces the activity of the GMP synthase Gua1 in budding yeast and the total G-nucleotide pool, leading to precipitous reductions in the GDP/GTP ratio and ATP level in vivo. gua1-G388D strongly reduces the rate of growth, impairs general protein synthesis, and derepresses translation of GCN4 mRNA, encoding a transcriptional activator of diverse amino acid biosynthetic enzymes. Although processing of pre-tRNA i Met and other tRNA precursors, and the aminoacylation of tRNA iMet are also strongly impaired in gua1-G388D cells, tRNA i GTP complex (TC) and the multifactor complex (MFC) required for translation initiation accumulate $10-fold in gua1-G388D cells and, to a lesser extent, in wild-type (WT) cells treated with 6-azauracil (6AU). Consistently, addition of an external supply of guanine reverts all the phenotypes of gua1-G388D cells, but not those of gua1-G388D Dhpt1 mutants unable to refill the internal GMP pool through the salvage pathway. These and other findings suggest that a defect in guanine nucleotide biosynthesis evokes a reduction in the rate of general protein synthesis by impairing multiple steps of the process, disrupts the gene-specific reinitiation mechanism for translation of GCN4 mRNA and has far-reaching effects in cell biology and metabolism.

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confidence: 99%

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

et al. 2011

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“…24 In a study in healthy volunteers, MPA induced a decrease in IMPDH type 1 expression but stable type 2 expression. 30 The rise in mRNA expression after day 6 in our study is presumably due to the MPA-induced inhibition of IMPDH activity. IMPDH mRNA expression is regulated by a negative feedback mechanism by guanine nucleotides.…”

Section: Discussionmentioning

confidence: 48%

Inosine Monophosphate Dehydrogenase Messenger RNA Expression Is Correlated to Clinical Outcomes in Mycophenolate Mofetil-Treated Kidney Transplant Patients, Whereas Inosine Monophosphate Dehydrogenase Activity Is Not

Sombogaard¹,

Peeters²,

Baan³

et al. 2009

Therapeutic Drug Monitoring

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Measurement of the pharmacodynamic biomarker inosine monophosphate dehydrogenase (IMPDH) activity in renal transplant recipients has been proposed to reflect the biological effect better than using pharmacokinetic parameters to monitor mycophenolate mofetil therapy. The IMPDH assays are however labor intensive and this complicates implementation into patient care. Quantification of IMPDH messenger RNA (mRNA) could form an attractive alternative. This study was designed to correlate IMPDH mRNA levels with IMPDH activity and clinical outcome in renal transplant recipients. From a cohort of 101 renal transplant patients, blood samples were drawn pre transplantation and at 4 times after transplantation. IMPDH activity, IMPDH type 1 and type 2 mRNA levels, and mycophenolic acid concentrations were measured and correlated to clinical outcomes. No correlation was found between IMPDH type 1 and type 2 mRNA levels and IMPDH activity in pre- and posttransplant samples. A significant increase in IMPDH mRNA levels was found between day 6 and day 140 after transplantation. IMPDH type 1 and type 2 mRNA levels before transplant showed a trend toward statistically significant higher levels in patients with an acute rejection (P = 0.052 and P = 0.058). After transplant, the IMPDH type 1 and type 2 mRNA levels were significantly lower in patients with an acute rejection (P = 0.026 and P = 0.007). We conclude that IMPDH mRNA levels do not correlate with IMPDH activity but are nevertheless correlated with acute rejections. Furthermore, although the regulation of the expression of the 2 isoforms is presumed to be different, in this study, the changes in the expression of type 1 mRNA closely paralleled those of type 2.

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“…Notably, it was confirmed that resting CB T cells are naive (25,28,38) and secrete lower cytokine levels than PBMCs (36). The proteins of the NFAT family play a major role in the transcriptional regulation of many cytokine genes (21Y24, 39).…”

Section: Discussionmentioning

confidence: 97%

“…In renal transplantation, CsA reduced MPA exposure by inhibiting its enterohepatic recirculation (34). Moreover, MPA concentrations correlate with its pharmacologic effects and with IMPDH inhibition; however, several studies showed a strong inter-patient variability in MPA exposure and IMPDH concentration (35,36). It has also been shown that MPA influences IMPDH1 expression within the dose interval in renal allograft patients (CsA) (37).…”

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confidence: 99%