Alteration of the C Fms Gene in a Blood Sample From a Thorotrast Individual

Collart, F.; Horio, Mitsuzo; Ra, Schlenker; Rl, Kathren; Huberman, Eliezer

doi:10.1097/00004032-199207000-00004

Cited by 9 publications

(8 citation statements)

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“…Many studies have shown that IMPDH activity is elevated in tumors and other actively proliferating tissues (3,4,(7)(8)(9)(10)(11)(12)(13)(14)(15). In some cases the elevated activity seems to stem from induction of the type II isoenzyme (9, 11, 12), although similar up-regulation of both isoforms in activated T-lymphocytes has also been reported (14).…”

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confidence: 92%

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Conformational Changes and Stabilization of Inosine 5′-Monophosphate Dehydrogenase Associated with Ligand Binding and Inhibition by Mycophenolic Acid

Nimmesgern

Fox

Fleming

et al. 1996

Journal of Biological Chemistry

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The effects of substrate, product, and inhibitor (mycophenolic acid) binding on the conformation and stability of hamster type II inosine 5-monophosphate dehydrogenase (IMPDH) have been examined. The protein in various states of ligand occupancy was compared by analyzing susceptibility to in vitro proteolysis, the degree of binding of a hydrophobic fluorescent dye, secondary structure content as determined by far-UV circular dichroism spectra, and urea-induced denaturation curves. These analysis methods revealed consistent evidence that IMPDH undergoes a local reorganization when IMP or XMP bind. NAD ؉ produced no such effect. In fact, no evidence was found for NAD ؉ binding independently of IMP. It is proposed that IM-PDH adopts an open conformation around its nucleotide binding sites in the absence of substrates and that binding of IMP stabilizes a closed conformation that has a higher affinity for NAD ؉ . The data also suggest the enzyme remains in the closed configuration throughout the catalytic steps and then reverts to the open conformation with XMP release, thereby consummating the enzyme cycle. Mycophenolic acid inhibition appeared to impart even greater stability. We propose that localized conformational changes occur during the normal and mycophenolic acid-inhibited reaction sequences of IMPDH.Inosine 5Ј-monophosphate dehydrogenase (IMPDH; 1 EC 1.1.1.205) catalyzes the conversion of IMP to XMP, the committed step in the de novo biosynthesis of guanine nucleotides (1-4). Now partially characterized from many organisms, IMPDH is well conserved with 35% or more sequence identity from bacterial and protozoan to human proteins (5, 6). Since the enzyme appears to be necessary for cellular replication, some view it as an attractive target for anti-microbial chemotherapy; however, others have recognized further therapeutic possibilities for IMPDH inhibition.Human and hamster possess two closely related isoenzymes (designated types I and II). In both species the isoforms share 84% (of 514 residues) sequence identity (5).2 The existence of similar isoenzymes in mammals suggests a subtle distinction of roles. Many studies have shown that IMPDH activity is elevated in tumors and other actively proliferating tissues (3,4,(7)(8)(9)(10)(11)(12)(13)(14)(15). In some cases the elevated activity seems to stem from induction of the type II isoenzyme (9, 11, 12), although similar up-regulation of both isoforms in activated T-lymphocytes has also been reported (14). These observations suggest that inhibition of IMPDH, or perhaps selective inhibition of individual isoforms, has potential for immunosuppressive or anti-neoplastic therapies. Indeed, inhibition of IMPDH in cultured cells results in decreased guanine nucleotide levels. Ultimately, this leads to the induction of differentiation in neoplastic cells (8) and the suppression of lymphocyte activation (16).Mycophenolic acid (MPA), an uncompetitive inhibitor of IMPDH that was originally identified in certain Penicillium cultures (17), is a potent immunosuppressant, bot...

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confidence: 92%

“…Indeed, inhibition of IMPDH in cultured cells results in decreased guanine nucleotide levels. Ultimately, this leads to the induction of differentiation in neoplastic cells (8) and the suppression of lymphocyte activation (16).…”

mentioning

confidence: 99%

Conformational Changes and Stabilization of Inosine 5′-Monophosphate Dehydrogenase Associated with Ligand Binding and Inhibition by Mycophenolic Acid

Nimmesgern

Fox

Fleming

et al. 1996

Journal of Biological Chemistry

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“…The abundance of the enzymatic activity is correlated with the rate of growth of mammalian cells (1)(2)(3). Antagonists of this family of enzymes, one of which is mycophenolic acid, serve as medically important antitumor, antimicrobial, and immunosuppressive agents (4).…”

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confidence: 99%

“…Characterization of two IMP dehydrogenase genes in mammalian cells has included an analysis of their promoters and the solution of a crystal structure of rodent IMP dehydrogenase in a complex with mycophenolic acid (5)(6)(7). Mammalian IMP dehydrogenase (IMPDH) 1 II is inducible in a post-transcriptional manner, in response to depressed guanine nucleotide pools (3,8). Saccharomyces cerevisiae has a family of four closely related genes, IMD1, IMD2 (formerly known as PUR5), IMD3, and IMD4, that encode potential IMP dehydrogenases.…”

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confidence: 99%

Regulation of an IMP Dehydrogenase Gene and Its Overexpression in Drug-sensitive Transcription Elongation Mutants of Yeast

Shaw¹,

Wilson²,

Smith³

et al. 2001

Journal of Biological Chemistry

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IMP dehydrogenase is a rate-limiting enzyme involved in the synthesis of GTP. In mammalian cells it is regulated with respect to growth rate and is the target of numerous therapeutic agents. Mutations in the RNA polymerase II elongation machinery render yeast sensitive to inhibitors of IMP dehydrogenase and defective in inducing transcription of one of the IMP dehydrogenase-encoding genes, IMD2. Here we show that loss of IMD2, but not IMD1, IMD3, or IMD4, conferred upon yeast the same drug sensitivity found in elongation mutants. We tested whether the drug sensitivity of elongation mutants is due to their inability to induce IMD2 by providing them with exogenous copies of the gene. In some elongation mutants, overexpression reversed drug sensitivity and a transcriptional defect. Overexpression in mutants with a more severe phenotype partially suppressed drug sensitivity but was inconsequential in reversing a defect in transcription. These findings suggest that the drug sensitivity of elongation mutants is largely but not solely attributable to defects in the ability to induce IMD2, because transcription is compromised even when IMD2 mRNA levels are adequate. We describe two DNA sequence elements in the promoter of the gene that regulate it. We also found that IMD2 mRNA abundance is coupled to cell growth rate. These findings show that yeast possess a conserved system that gauges nucleotide pools and cell growth rate and responds through a uniquely regulated member of the IMD gene family.

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“…As a negative control, the assay was run in the absence of a precipitating antibody, which resulted in no amplification products for all three of the queried genes (lane 4 of each gel). In addition, PCR for the promoter of type II IMP dehydrogenase, a gene that has not been shown to be responsive to TGF-b or BMP stimulation, yet is critical for mycophenolic acid induced-HL-60 cell differentiation (Collart and Huberman, 1990), resulted in no amplification from the ChIP-recovered DNA (data not shown). Analysis of PMA-induced OPN, Hex and Id2 gene expression by rtPCR (lower panel) revealed that expression patterns are similar to the patterns of Smad6 binding to their respective promoters.…”

Section: Prkx Activity During Hl-60 Differentiation D Glesne and E Humentioning

confidence: 98%

Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation

Glesne

Huberman

2006

Oncogene

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To gain insight into the function of human protein kinase X (PrKX), a signal-transduction protein required for macrophage differentiation, we identified regulatory subunit I alpha of protein kinase A, T54 and Smad6 as partners for this protein using a yeast two-hybrid interaction screen. Interactions between PrKX and these proteins were substantiated by co-immunoprecipitation. Interaction between Smad6 and PrKX was also confirmed in human myeloid HL-60 cells following their phorbol 12-myristate 13-acetate (PMA)-induced differentiation into macrophages. In vitro phosphorylation assays demonstrated that PrKX phosphorylates Smad6 at a serine residue. Mutagenesis of this site resulted in abrogation of PrKX phosphorylation. Both PrKX and Smad6 were shown to be co-localized to the nuclear compartment of HL-60 cells during their macrophage differentiation where PrKX levels are induced and Smad6 protein levels remain relatively constant while levels of serine phosphorylation of Smad6 increase. By using in vitro electrophoretic mobility shift assays and in vivo chromatin immunoprecipitation, we also demonstrate that during macrophage differentiation Smad6 displays an increased binding to the human osteopontin, Id2, and Hex gene promoters, which correlates to an observed increased expression of these genes. Finally, vector-based RNA interference experiments established that both Smad6 and PrKX proteins are required for PMA-induced cell attachment and spreading.

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Alteration of the C Fms Gene in a Blood Sample From a Thorotrast Individual

Cited by 9 publications

References 0 publications

Conformational Changes and Stabilization of Inosine 5′-Monophosphate Dehydrogenase Associated with Ligand Binding and Inhibition by Mycophenolic Acid

Conformational Changes and Stabilization of Inosine 5′-Monophosphate Dehydrogenase Associated with Ligand Binding and Inhibition by Mycophenolic Acid

Regulation of an IMP Dehydrogenase Gene and Its Overexpression in Drug-sensitive Transcription Elongation Mutants of Yeast

Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation

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