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PubMed1996

An ABC transporter is essential for resistance to the antitumor agent mithramycin in the producer Streptomyces argillaceus.

Mithramycin is an antitumor antibiotic synthesized by Streptomyces argillaceus. This producer strain is highly resistant in vivo to mithramycin (MIC 100 micrograms/ml) but sensitive to the related drugs chromomycin and olivomycin (MIC 10 micrograms/ml). From a genomic library of S. argillaceus DNA two cosmid clones were isolated which confer a high level of resistance to mithramycin on S. albus. The resistance genes were mapped by subcloning to a 3.9-kb PstI-PvuII fragment. DNA sequence analysis of this fragment revealed one incomplete and three complete open reading frames. Subcloning experiments demonstrated that resistance to mithramycin is mediated by the genes mtrA and mtrB. The mtrA gene can potentially encode an ATP-binding protein of the ABC transporter superfamily, containing one nucleotide-binding domain and showing similarity with other ABC transporters involved in resistance to daunorubicin, oleandomycin and tetronasin in their respective producer strains. The mtrB gene codes for an integral membrane protein with six putative transmembrane helices. A mithramycin-sensitive mutant was generated in a gene replacement experiment by disrupting the mtrA gene, thus demonstrating that the system encoded by the mtrAB genes is essential for conferring resistance to mithramycin in S. argillaceus.

ATP-Binding Cassette Transporters↗
PubMed1990

Salmon calcitonin in the acute management of hypercalcemia.

Salmon calcitonin has been used for the management of acute hypercalcemia for the past several years. Unlike other hypocalcemic agents, it is effective within 2 hours after first dosing. This pharmacologic agent shows peak effect at 24-48 hours and has a duration of action of 4-7 days in most cases. Its effectiveness may diminish thereafter despite continuous administration (the so-called "escape phenomenon"). Salmon calcitonin has been shown to be effective in the management of acute hypercalcemia due to a variety of causes, and, because of its low toxicity profile, it may be administered to patients with congestive heart failure or azotemia. Salmon calcitonin is also an analgesic agent in patients with pain associated with bone metastases and may be used in conjunction with other hypocalcemic agents such as mithramycin, the bisphosphonates, or gallium nitrate to prolong the clinical response to more than 1 week. Salmon calcitonin is therefore effective and safe in the management of acute hypercalcemia.

Adrenal Cortex Hormones↗
PubMed1976

The study of variability and strain selection in Streptomyces atroolivaceus. III. Isolation and preliminary characteristics of mutants impaired in the biosynthesis of mithramycin.

Mutants of Streptomyces atroolivaceus blocked in the biosynthesis of mithramycin were isolated both by natural selection and after treatment with mutagenic factors (UV and gamma rays, nitrous acid). Both physical factors were more effective than nitrous acid. The selection was complicated by a high instability of isolates, out of which 20-80% (depending on their origin) reversed spontaneously to the parent type. The primary screening (selection of morphological variants and determination of their activity using the method of agar blocks) made it possible to detect only potentially non-productive strains; however, the final selection had to be performed always under submerged conditions. Fifty-four stable non-productive mutants were divided, according to results of the chromatographic analysis, in five groups differing in production of six biologically inactive metabolites (compounds A-H). The mutants did not accumulate chromomycinone, chromocyclomycin and chromocyclin. On mixed cultivation none of the pairs of mutants was capable of cosynthesis of mithramycin or new compounds differing from standard metabolites. Possible causes of the above results are discussed.

Cobalt Radioisotopes↗
PubMed2000

Characterization of two glycosyltransferases involved in early glycosylation steps during biosynthesis of the antitumor polyketide mithramycin by Streptomyces argillaceus.

A 2,580-bp region of the chromosome of Streptomyces argillaceus, the producer of the antitumor polyketide mithramycin, was sequenced. Analysis of the nucleotide sequence revealed the presence of two genes (mtmGIII and mtmGIV) encoding proteins that showed a high degree of similarity to glycosyltransferases involved in the biosynthesis of various antibiotics and antitumor drugs. Independent insertional inactivation of both genes produced mutants that did not synthesize mithramycin but accumulated several mithramycin intermediates. Both mutants accumulated premithramycinone, a non-glycosylated intermediate in mithramycin biosynthesis. The mutant affected in the mtmGIII gene also accumulated premithramycin A1, which contains premithramycinone as the aglycon unit and a D-olivose attached at C-12a-O. These experiments demonstrate that the glycosyltransferases MtmGIV and MtmGIII catalyze the first two glycosylation steps in mithramycin biosynthesis. A model is proposed for the glycosylation steps in mithramycin biosynthesis.

Amino Acid Sequence↗
PubMed2005

Regulation of human resistin gene expression in cell systems: an important role of stimulatory protein 1 interaction with a common promoter polymorphic site.

AIMS/HYPOTHESIS: Resistin is an adipokine that might link obesity and insulin resistance. A common polymorphism of the human resistin gene, -420C >G, is a major determinant of plasma resistin concentrations as well as resistin mRNA expression in human adipose tissue. In this study, we investigated the regulatory mechanism by which this polymorphism affects resistin expression. METHODS: Electrophoretic mobility shift assay was performed to identify the transcription factors binding to the -420G region. Transient transfection and reporter assay were used to measure promoter activities of the resistin gene. The binding ability of stimulatory protein 1 (Sp1) in response to adipocyte differentiation or high glucose concentrations was also measured. RESULTS: Sp1 and stimulatory protein 3 (Sp3) specifically bound to the region around -420G of the human resistin gene. Overexpression of Sp1 increased the promoter activity regardless of -420 genotypes, while the promoter activity of the -420G construct was two-fold higher than that of the -420C construct. In contrast, overexpression of Sp3 scarcely increased the promoter activity. The binding ability of Sp1 to the -420G region was increased in response to adipocyte differentiation. Mithramycin A, an inhibitor of DNA binding of Sp1, reduced the effect of high glucose on transcription induction of the resistin gene in adipocytes. CONCLUSIONS/INTERPRETATION: These results suggest that Sp1 is an important factor regulating transcription of human resistin gene. A common polymorphism of the human resistin promoter, -420C >G, is critical for the binding of Sp1 and modulates the transcriptional activity of the resistin gene by changing the binding ability of Sp1. In addition, Sp1 may be involved in the increase of resistin expression by hyperglycaemia.

3T3 Cells↗
PubMed2006

The aureolic acid family of antitumor compounds: structure, mode of action, biosynthesis, and novel derivatives.

Members of the aureolic acid family are tricyclic polyketides with antitumor activity which are produced by different streptomycete species. These members are glycosylated compounds with two oligosaccharide chains of variable sugar length. They interact with the DNA minor groove in high-GC-content regions in a nonintercalative way and with a requirement for magnesium ions. Mithramycin and chromomycins are the most representative members of the family, mithramycin being used as a chemotherapeutic agent for the treatment of several cancer diseases. For chromomycin and durhamycin A, antiviral activity has also been reported. The biosynthesis gene clusters for mithramycin and chromomycin A(3) have been studied in detail by gene sequencing, insertional inactivation, and gene expression. Most of the biosynthetic intermediates in these pathways have been isolated and characterized. Some of these compounds showed an increase in antitumor activity in comparison with the parent compounds. A common step in the biosynthesis of all members of the family is the formation of the tetracyclic intermediate premithramycinone. Further biosynthetic steps (glycosylation, methylations, acylations) proceed through tetracyclic intermediates which are finally converted into tricyclic compounds by the action of a monooxygenase, a key event for the biological activity. Heterologous expression of biosynthetic genes from other aromatic polyketide pathways in the mithramycin producer (or some mutants) led to the isolation of novel hybrid compounds.

Antibiotics, Antineoplastic↗
PubMed2000

Sex chromosome evolution in fish: the formation of the neo-Y chromosome in Eigenmannia (Gymnotiformes).

Chromosomes of a species of Eigenmannia presenting a X1X1X2X2:X1X2Y sex chromosome system, resulting from a Y-autosome Robertsonian translocation, were analyzed using the C-banding technique, chromomycin A3 (CMA3) and mithramycin (MM) staining and in situ digestion by the restriction endonuclease AluI. A comparison of the metacentric Y chromosome of males with the corresponding acrocentrics in females indicated that a C-band-positive, CMA3/MM-fluorescent and AluI digestion-resistant region had been lost during the process of translocation, resulting in a diminution of heterochromatin in the males. It is hypothesized that the presence of a smaller amount of G + C-rich heterochromatin in the sex chromosomes of the heteromorphic sex when compared with the homomorphic sex may be associated with the sex determination mechanism in this species and may be a more widely occurring phenomenon in fish with differentiated sex chromosomes than was initially thought.

Animals↗
PubMed2002

Functional role of Egr-1 mediating VEGF-induced tissue factor expression in the retinal capillary endothelium.

PURPOSE: To investigate the causal relationship between VEGF and tissue factor (TF) expression, and its intracellular signaling in the retinal capillary endothelium both in vitro and in vivo. METHODS: TF mRNA and protein expression in cultured bovine retinal capillary endothelial cells (BRECs) were detected by RT-PCR and western blotting. The expression and subcellular localization of Egr-1 were analyzed by immunocytochemistry and western blotting. Involvement of p44/p42 MAPK pathway in this signaling was assessed using PD98059. Electrophoretic mobility shift assay (EMSA) was performed using human TF Egr-1/Sp-1 overlapping promoter region (-85 to -70). Decoy oligonucleotide was transfected into BRECs to clarify the critical transcription factor mediating VEGF-induced TF gene expression. To evaluate the importance of GC rich region in VEGF-induced TF protein expression in rat retinas, Mithramycin was intraperitoneally administered. RESULTS: VEGF stimulated TF mRNA and protein expression in cultured BRECs, reaching maximal effect after 4 h and 10 h, respectively. VEGF activated transcription factor Egr-1 within 60 min. Inactivation of Egr-1 by PD98059 resulted in the prohibition of VEGF-induced TF gene expression. EMSA revealed the increment of Egr-1 binding with TF promoter region by displacing Sp1 after treatment with VEGF. Transfection of the Egr-1/Sp-1 overlapping decoy into BRECs inhibited VEGF-dependent TF gene expression. Mithramycin almost completely suppressed VEGF-induced TF protein expression in retinal capillary system in vivo (80%, p<0.01). CONCLUSION: Transcription factor Egr-1, which lies downstream of p44/p42 MAPK, critically mediates VEGF-dependent TF expression in the retinal capillary endothelium.

Animals↗
PubMed2001

The mtmVUC genes of the mithramycin gene cluster in Streptomyces argillaceus are involved in the biosynthesis of the sugar moieties.

Mithramycin is a glycosylated aromatic polyketide produced by Streptomyces argillaceus, and is used as an antitumor drug. Three genes (mtmV, mtmU and mtmC) from the mithramycin gene cluster have been cloned, and characterized by DNA sequencing and by analysis of the products that accumulate in nonproducing mutants, which were generated by insertional inactivation of these genes. The mtm V gene codes for a 2,3-dehydratase that catalyzes early and common steps in the biosynthesis of the three sugars found in mithramycin (D-olivose, D-oliose and D-mycarose); its inactivation caused the accumulation of the nonglycosylated intermediate premithramycinone. The mtmU gene codes for a 4-ketoreductase involved in D-oliose biosynthesis, and its inactivation resulted in the accumulation of premithramycinone and premithramycin A , the first glycosylated intermediate which contains a D-olivose unit. The third gene, mtmC, is involved in D-mycarose biosynthesis and codes for a C-methyltransferase. Two mutants with lesions in the mtmC gene accumulated mithramycin intermediates lacking the D-mycarose moiety but containing D-olivose units attached to C-12a in which the 4-keto group is unreduced. This suggests that mtmC could code for a second enzyme activity, probably a D-olivose 4-ketoreductase, and that the glycosyltransferase responsible for the incorporation of D-olivose (MtmGIV) shows some degree of flexibility with respect to its sugar co-substrate, since the 4-ketoanalog is also transferred. A pathway is proposed for the biosynthesis of the three sugar moieties in mithramycin.

Carbohydrate Sequence↗
PubMed1999

Analysis of two chromosomal regions adjacent to genes for a type II polyketide synthase involved in the biosynthesis of the antitumor polyketide mithramycin in Streptomyces argillaceus.

Mithramycin is an aromatic antitumour polyketide synthesized by Streptomyces argillaceus. Two chromosomal regions located upstream and downstream of the locus for the mithramycin type II polyketide synthase were cloned and sequenced. Analysis of the sequence revealed the presence of eight genes encoding three oxygenases (mtmOI, mtmOII and mtmOIII), three reductases (mtmTI, mtmTII and mtmTIII), a cyclase (mtm Y) and an acyl CoA ligase (mtmL). The three oxygenase genes were each inactivated by gene replacement. Inactivation of one of them (mtmOII) generated a non-producing mutant, while inactivation of the other two (mtmOl and mtmOIII) did not affect the biosynthesis of mithramycin. The mtmOII gene may code for an oxygenase responsible for the introduction of oxygen atoms at early steps in the biosynthesis of mithramycin leading to 4-demethylpremithramycinone. One of the reductases may be responsible for reductive cleavage of an intermediate from an enzyme and another for the reduction of a keto group in the side-chain of the mithramycin aglycon moiety. A hypothetical biosynthetic pathway showing in particular the involvement of oxygenase MtmOII and of various other gene products in mithramycin biosynthesis is proposed.

Amino Acid Sequence↗
PubMed2004

Effect of complex formation between Zn2+ ions and the anticancer drug mithramycin upon enzymatic activity of zinc(II)-dependent alcohol dehydrogenase.

Mithramycin (MTR), a member of the aureolic group of anticancer antibiotics, is a drug that supposedly acts via the inhibition of transcription. It binds to bivalent cations such as Mg(2+) and Zn(2+). In this paper, we report the association of MTR with Zn(2+), a biologically important bivalent cation whose coordination property leads to its important role as a cofactor in different enzymes and nucleosomal DNA-binding proteins. First, we have characterized the complex formation between MTR and Zn(2+) using spectroscopic methods. In the second part, we have examined the effect of the association of Zn(2+) with MTR on the enzymatic activity of a typical zinc(II)-dependent alcohol dehydrogenase (ADH) from yeast. Our data show that MTR forms a single complex with Zn(2+) in a mole ratio of 2:1 in terms of MTR:Zn(2+). We also observe a negative effect for the preincubation of ADH with MTR upon the enzymatic activity. These results indicate that MTR induced structural changes in the enzyme as a sequel to its complex formation with Zn(2+) present in the enzyme, thereby leading to a loss of enzymatic activity.

Alcohol Dehydrogenase↗