IMP dehydrogenase, an enzyme linked with proliferation and malignancy

Jackson, Robert; Weber, George; Morris, Harold P.

doi:10.1038/256331a0

Cited by 343 publications

(208 citation statements)

References 15 publications

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“…protein; regenerating 12.6 ± 0.6,umol/h per mg of protein. After 18h, activity slowly declined, as found in the earlier study (Jackson et al, 1975). At no time did activity in the liver of sham-operated animals differ significantly from normal values of unoperated rats.…”

Section: Regenerating Liversupporting

confidence: 77%

“…The correlation between IMP dehydrogenase activity and cell proliferation, demonstrated in the hepatoma spectrum (Jackson et al, 1975), was further emphasized by the results of the tissue-distribution study. In particular, the high activities found in thymus and spleen, and to a lesser extent in bone marrow and testis, indicated the importance of this enzyme for cell division.…”

Section: Imp Dehydrogenase In Malignant Tissuesmentioning

confidence: 90%

“…In addition to being inhibited by natural nucleotides, IMP dehydrogenase was a target enzyme for a number of anti-tumour drugs, including 6-thioinosinic acid, mycophenolic acid and 6-chloropurine ribonucleotide (Atkinson et al, 1963;Sweeney et al, 1972;Anderson & Sartorelli, 1969). We have recently reported (Jackson et al, 1975) increased IMP dehydrogenase activity in conditions of normal and malignant cell proliferation. The present paper describes new results about partial purification, properties and comparative studies of this enzyme in developing and regenerating liver, and in trans-1 plantable hepatomas and kidney tumours of the rat.…”

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confidence: 98%

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Partial purification, properties and regulation of inosine 5′-phosphate dehydrogenase in normal and malignant rat tissues

Jackson¹,

Morris²,

Weber³

1977

Biochemical Journal

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IMP dehydrogenase (EC 1.2.1.14) was purified 180-fold from rat liver and from the transplantable rat hepatoma 3924A. The enzymes from the two sources were apparently identical; they exhibited hyperbolic saturation kinetics and an ordered, sequential mechanism, and were subject to inhibition by a number of purine nucleotides. Km values for the substrates, IMP and NAD+, were 12 and 24pUM respectively. IMP dehydrogenase activity in a spectrum of rat hepatomas was increased, relative to normal liver, by 2.5-13-fold; these increases correlated with tumour growth rate. Activity in two rat kidney tumours was increased 3-fold relative to that in normal renal cortex; control of activity of this enzyme is apparently altered in neoplastic cells. After partial hepatectomy, IMP dehydrogenase activity began to rise 6h after operation, reaching a peak of580 % ofnormal activity by 18h. Activity in neonatal liver, however, was only slightly higher than that in the adult. Organ-distribution studies showed highest enzyme activities in spleen and thymus. In livers of rats starved for 3 days, where all enzymes, except those involved in gluconeogenesis, showed decreased activity, IMP dehydrogenase activity was increased; this change was accompanied by a rise in hepatic GTP concentrations. It is concluded that IMP dehydrogenase is a key enzyme in the regulation of GTP production, and thus involved in regulation ofnucleic acid biosynthesis. The increased activity ofIMP dehydrogenase in liver of starved rats may be related to the requirement for GTP for gluconeogenesis.

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Section: Regenerating Liversupporting

confidence: 77%

Section: Imp Dehydrogenase In Malignant Tissuesmentioning

confidence: 90%

mentioning

confidence: 98%

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Partial purification, properties and regulation of inosine 5′-phosphate dehydrogenase in normal and malignant rat tissues

Jackson¹,

Morris²,

Weber³

1977

Biochemical Journal

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“…The protein encoded by IMPDH2 catalyzes the first step in formation of guanine ribonucleotides from inosine monophosphate, which is important for cell proliferation. IMPDH activity correlates positively with increased proliferation of both normal and malignant cells 49 as well as malignant transformation. 49,50 Previous reports have shown that depletion of guanine nucleotide pools, after inhibition of IMPDH by mycophenolic acid or mizoribine, potently inhibits cell cycle progression by arresting activated T lymphocytes in the G 1 phase of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

“…IMPDH activity correlates positively with increased proliferation of both normal and malignant cells 49 as well as malignant transformation. 49,50 Previous reports have shown that depletion of guanine nucleotide pools, after inhibition of IMPDH by mycophenolic acid or mizoribine, potently inhibits cell cycle progression by arresting activated T lymphocytes in the G 1 phase of the cell cycle. 51 HPRT1 is essential for the purine nucleotide salvage pathway and, like IMPDH2, plays an essential role in mercaptopurine activation.…”

Section: Discussionmentioning

confidence: 99%

Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis

Zaza

Yang

Kager

et al. 2004

Blood

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Because de novo purine synthesis (DNPS) is a target of widely used antileukemic agents (eg, methotrexate, mercaptopurine), we determined the rate of DNPS and the expression of genes involved in purine metabolism in different subtypes of acute lymphoblastic leukemia (ALL). Among 113 children with newly diagnosed ALL, lymphoblasts with the TEL-AML1 translocation had significantly lower DNPS than all other genetic subtypes of B-lineage ALL or T-lineage ALL (352 ؎ 57 versus 1001 ؎ 31 or versus 1315 ؎ 76 fmol/nmol/h, P < .0001). By assessing the expression of 82 genes involved in purine metabolism (KEGG pathway database) in ALL blasts from 38 patients with B-lineage ALL (14 with TEL-AML1, 24 without), we identified 16 genes that were differentially expressed in TEL-AML1-positive and TEL-AML1-negative ALL (P < .001, false discovery rate [FDR] ‫؍‬ 5%). The pattern of expression of these 16 genes discriminated TEL-AML1-positive ALL with a true accuracy of 84% in an independent test set (n ‫؍‬ 17, confidence interval 70% to 94%, P < .001). Western blots of selected genes documented corresponding levels of the proteins encoded. Differentially expressed genes included HPRT, IMPDH, PAICS, and GART, all of which were expressed at a significantly lower level in TEL-AML1 ALL. These findings have established that TEL-AML1 ALL has significantly lower de novo purine synthesis and differential expression of genes involved in purine metabolism. ( IntroductionPediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising different immunophenotypes and various genetic subtypes caused by chromosomal translocations with aberrant gene fusions and inappropriate expression of oncogenes. These genetic abnormalities have important prognostic and therapeutic implications, but the underlying mechanisms are not fully understood. 1 De novo purine synthesis (DNPS) is higher in ALL cells compared with normal bone marrow cells and peripheral blood lymphocytes, and T-lineage ALL has higher DNPS than B-lineage ALL. 2,3 It is not known, however, whether DNPS differs among the genetic subtypes of B-lineage ALL.Nucleotides play a key role in many biochemical processes related to their importance as DNA and RNA precursors, energy carriers, coenzyme components, and metabolic regulators. 4 Cells obtain purine nucleotides through 2 separate metabolic pathways, de novo purine synthesis and salvage of extracellular purine bases and nucleotides. DNPS and several enzymes involved in the purine metabolism pathway are important targets for antimetabolites (eg, mercaptopurine and methotrexate) that are the cornerstone of continuation therapy for childhood ALL. 1 DNPS is a complex pathway in which nucleotides are synthesized from amino acids and tetrahydrofolate in a multienzymatic process, starting with phosphoribosyl pyrophosphate (PRPP), primarily formed from ribose-5-phosphate (from the pentose phosphate pathway) and adenosine triphosphate (ATP). 4 Previous studies have shown that the pattern of gene expression in ALL blasts differs among ...

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