The Experts below are selected from a list of 1107 Experts worldwide ranked by ideXlab platform
Olivier Berteau - One of the best experts on this subject based on the ideXlab platform.
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Thiostrepton tryptophan methyltransferase expands the chemistry of radical sam enzymes
Nature Chemical Biology, 2012Co-Authors: Alhosna Benjdia, Olivier Berteau, Stephane Pierre, Alain Guillot, Corine Sandstrom, Philippe LangellaAbstract:TsrM, a member of the radical SAM enzyme family, is shown to catalyze tryptophan methylation en route to Thiostrepton A with the help of a methylcobalamin cofactor and without generating the canonical 5-deoxyadenosyl radical.
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Thiostrepton tryptophan methyltransferase expands the chemistry of radical SAM enzymes
Nature Chemical Biology, 2012Co-Authors: Stephane Pierre, Alhosna Benjdia, Alain Guillot, Corine Sandstrom, Philippe Langella, Olivier BerteauAbstract:Methylation is among the most widespread chemical modifications encountered in biomolecules and has a pivotal role in many major biological processes. In the biosynthetic pathway of the antibiotic Thiostrepton A, we identified what is to our knowledge the first tryptophan methyltransferase. We show that it uses unprecedented chemistry to methylate inactivated sp(2)-hybridized carbon atoms, despite being predicted to be a radical SAM enzyme.
Andrei L. Gartel - One of the best experts on this subject based on the ideXlab platform.
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Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PLoS One 2009; 4: e5592
2016Co-Authors: Marianna Halasi, Andrei L. GartelAbstract:Forkhead box M1 (FoxM1) oncogenic transcription factor represents an attractive therapeutic target in the fight against cancer, because it is overexpressed in a majority of human tumors. Recently, using a cell-based assay system we identified thiazole antibiotic Siomycin A as an inhibitor of FoxM1 transcriptional activity. Here, we report that structurally similar thiazole antibiotic, Thiostrepton also inhibits the transcriptional activity of FoxM1. Furthermore, we found that these thiopeptides did not inhibit the transcriptional activity of other members of the Forkhead family or some non-related transcription factors. Further experiments revealed that thiazole antibiotics also inhibit FoxM1 expression, but not the expression of other members of the Forkhead box family. In addition, we found that the thiazole antibiotics efficiently inhibited the growth and induced potent apoptosis in human cancer cell lines of different origin. Thiopeptide-induced apoptosis correlated with the suppression of FoxM1 expression, while overexpression of FoxM1 partially protected cancer cells from the thiazole antibiotic-mediated cell death. These data suggest that Siomycin A and Thiostrepton may specifically target FoxM1 to induce apoptosis in cancer cells and FoxM1 inhibitors/thiazole antibiotics could be potentially developed as novel anticancer drugs against human neoplasia
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Review Article Suppression of the Oncogenic Transcription Factor FOXM1 by Proteasome Inhibitors
2016Co-Authors: Andrei L. GartelAbstract:which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The oncogenic transcription factor FOXM1 is one of the key regulators of tumorigenesis. We found that FOXM1 upregulates its own transcription and its protein stability depends on its interaction with the chaperone nucleophosmin. We also determined that FOXM1 is negatively regulated by the tumor suppressor p53. We identified the thiazole antibiotics Siomycin A and Thiostrepton as inhibitors of transcriptional activity and FOXM1 expression via proteasome inhibition. In addition, we found that all tested proteasome inhibitors target FOXM1. We showed synergy between Thiostrepton and bortezomib in different human cancer cell lines and in vivo.We generated isogenic human cancer cell lines of different origin with wild-type p53 or p53 knockdown and we demonstrated that proteasome inhibitors induce p53-independent apoptosis in these cells. Using RNA-interference or proteasome inhibitors to inhibit FOXM1 we found that suppression of FOXM1 sensitized human cancer cells to apoptosis induced by DNA-damaging agents or oxidative stress. We encapsulated Thiostrepton into micelle-nanoparticles and after injection we detected accumulation of nanoparticles in tumors and in the livers of treated mice. This treatment led to inhibition of human xenograft tumor growth in nude mice. Our data indicate that targeting FOXM1 increases apoptosis and inhibits tumor growth. 1
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Suppression of the Oncogenic Transcription Factor FOXM1 by Proteasome Inhibitors
Hindawi Limited, 2014Co-Authors: Andrei L. GartelAbstract:The oncogenic transcription factor FOXM1 is one of the key regulators of tumorigenesis. We found that FOXM1 upregulates its own transcription and its protein stability depends on its interaction with the chaperone nucleophosmin. We also determined that FOXM1 is negatively regulated by the tumor suppressor p53. We identified the thiazole antibiotics Siomycin A and Thiostrepton as inhibitors of transcriptional activity and FOXM1 expression via proteasome inhibition. In addition, we found that all tested proteasome inhibitors target FOXM1. We showed synergy between Thiostrepton and bortezomib in different human cancer cell lines and in vivo. We generated isogenic human cancer cell lines of different origin with wild-type p53 or p53 knockdown and we demonstrated that proteasome inhibitors induce p53-independent apoptosis in these cells. Using RNA-interference or proteasome inhibitors to inhibit FOXM1 we found that suppression of FOXM1 sensitized human cancer cells to apoptosis induced by DNA-damaging agents or oxidative stress. We encapsulated Thiostrepton into micelle-nanoparticles and after injection we detected accumulation of nanoparticles in tumors and in the livers of treated mice. This treatment led to inhibition of human xenograft tumor growth in nude mice. Our data indicate that targeting FOXM1 increases apoptosis and inhibits tumor growth
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Thiazole antibiotics inhibit FoxM1-dependent transcription and FoxM1 expression.
2013Co-Authors: Uppoor G. Bhat, Marianna Halasi, Andrei L. GartelAbstract:(A) The chemical structure of the thiazole antibiotic, Thiostrepton that differs from Siomycin A by only two residues (Thiostrepton-R1-R2: Isoleucine-alanine; Siomycin- R1-R2: valine-dehydroalanine). (B) Luciferase assays after treatment of the C3-Luc2.3-FoxO1 cell line with the combination of either 1 µg/mL doxycycline (Doxy) or 300 nM tamoxifen (Tam) and 3 µM of Siomycin A (Sio) or Thiostrepton (Tio), respectively revealed that Thiostrepton is also a negative regulator of FoxM1 transcriptional activity and thiazole antibiotics inhibit FoxM1 transcriptional activity among the Forkhead family members. (C) Thiazole antibiotics downregulated FoxM1 protein levels, but not FoxA1, FoxO1 and FoxO3a levels as detected by immunoblotting. (D) The HCT116-p53RE-Luc cell line, which stably expressing firefly luciferase under the control of multiple p53 response elements treated with the indicated concentration of Siomycin A or Thiostrepton. After overnight treatment the luciferase activity was measured. (E) SW480 colon cancer cell line was transiently transfected with the Tcf/Lef-dependent TOPFlash and the control FOPFlash constructs. Twenty-four hrs following transfection the cells were treated with 3 µM of Siomycin A or Thiostrepton. The next day the luciferase activity was measured. (F) A549 lung cancer cells were transiently transfected with the GLI-dependent GLIBS-Luc, the control miniTK reporter constructs and the GLI expression plasmid. Cells were treated with the indicated concentration of the thiopeptides 24 hrs after transfection and the luciferase activity was measured the following day. Bars in B, D–F are representative mean values of triplicate experiments+/−SD.
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Overexpression of FoxM1 partially protects cancer cell lines from thiazole antibiotic-induced apoptosis.
2013Co-Authors: Uppoor G. Bhat, Marianna Halasi, Andrei L. GartelAbstract:(A) Immunoblot analysis after treatment with Siomycin A revealed close correlation between downregulation of FoxM1 and induction of apoptosis. (B) Following treatment with Thiostrepton, thiopeptide-induced apoptosis and inhibition of FoxM1 protein expression are more prominent in the presence of cyclohexamide (Chx) as depicted by immunoblotting for FoxM1 and cleaved caspase-3. (C) The expression of endogenous FoxM1 decreased in a time-dependent fashion in the presence of Thiostrepton and Chx, while the levels of exogenous FoxM1 were not affected. Overexpression of FoxM1 protected against cell death induced by Thiostrepton as detected by immunoblotting for cleaved caspase-3. (D) FoxM1 overexpressing cells were resistant to the treatment with increasing amount of Siomycin A as analyzed by immunoblotting for cleaved caspase-3. (E) Immunoblot analysis revealed that overexpression of FoxM1 also protected against Siomycin A-induced apoptosis in the presence of Chx.
Stephane Pierre - One of the best experts on this subject based on the ideXlab platform.
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Thiostrepton tryptophan methyltransferase expands the chemistry of radical sam enzymes
Nature Chemical Biology, 2012Co-Authors: Alhosna Benjdia, Olivier Berteau, Stephane Pierre, Alain Guillot, Corine Sandstrom, Philippe LangellaAbstract:TsrM, a member of the radical SAM enzyme family, is shown to catalyze tryptophan methylation en route to Thiostrepton A with the help of a methylcobalamin cofactor and without generating the canonical 5-deoxyadenosyl radical.
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Thiostrepton tryptophan methyltransferase expands the chemistry of radical SAM enzymes
Nature Chemical Biology, 2012Co-Authors: Stephane Pierre, Alhosna Benjdia, Alain Guillot, Corine Sandstrom, Philippe Langella, Olivier BerteauAbstract:Methylation is among the most widespread chemical modifications encountered in biomolecules and has a pivotal role in many major biological processes. In the biosynthetic pathway of the antibiotic Thiostrepton A, we identified what is to our knowledge the first tryptophan methyltransferase. We show that it uses unprecedented chemistry to methylate inactivated sp(2)-hybridized carbon atoms, despite being predicted to be a radical SAM enzyme.
Charles J Thompson - One of the best experts on this subject based on the ideXlab platform.
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ligand induced changes in the streptomyces lividans tipal protein imply an alternative mechanism of transcriptional activation for merr like proteins
Biochemistry, 2001Co-Authors: Mark L Chiu, Takaaki Katoh, Patrick H Viollier, Jeremy J Ramsden, Charles J ThompsonAbstract:TipAL is a Streptomyces transcriptional activator assigned to the MerR/SoxR family based both on homology within its putative DNA recognition domain and the fact that its operator binding sites lie within a region of its promoter normally occupied by RNA polymerase. The tipA gene is also independently translated as the C-terminal ligand-binding domain of TipAL (TipAS; residues 111−254). Both TipAS and TipAL share broad recognition specificity for cyclic thiopeptide antibiotics. The molecular mechanism by which TipAL catalyzes prokaryotic transcriptional activation at the tipA promoter (ptipA) in response to Thiostrepton was studied using a combination of analytical ultracentrifugation (AU), circular dichroism (CD), optical waveguide lightmode spectroscopy (OWLS; a sensitive in situ binding assay), and mutational analyses. AU showed that TipAL, but not TipAS, was a dimer in solution in the presence or absence of Thiostrepton. This indicated that activation of TipAL by Thiostrepton was not mediated by chang...
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broad spectrum thiopeptide recognition specificity of the streptomyces lividans tipal protein and its role in regulating gene expression
Journal of Biological Chemistry, 1999Co-Authors: Mark L Chiu, Marc Folcher, Takaaki Katoh, Anna Maria Puglia, Jiri Vohradsky, Bongsik Yun, Haruo Seto, Charles J ThompsonAbstract:Microbial metabolites isolated in screening programs for their ability to activate transcription of the tipA promoter (ptipA) in Streptomyces lividans define a class of cyclic thiopeptide antibiotics having dehydroalanine side chains ("tails"). Here we show that such compounds of heterogeneous primary structure (representatives tested: Thiostrepton, nosiheptide, berninamycin, promothiocin) are all recognized by TipAS and TipAL, two in-frame translation products of the tipA gene. The N-terminal helix-turn-helix DNA binding motif of TipAL is homologous to the MerR family of transcriptional activators, while the C terminus forms a novel ligand-binding domain. ptipA inducers formed irreversible complexes in vitro and in vivo (presumably covalent) with TipAS by reacting with the second of the two C-terminal cysteine residues. Promothiocin and Thiostrepton derivatives in which the dehydroalanine side chains were removed lost the ability to modify TipAS. They were able to induce expression of ptipA as well as the tipA gene, although with reduced activity. Thus, TipA required the thiopeptide ring structure for recognition, while the tail served either as a dispensable part of the recognition domain and/or locked thiopeptides onto TipA proteins, thus leading to an irreversible transcriptional activation. Construction and analysis of a disruption mutant showed that tipA was autogenously regulated and conferred thiopeptide resistance. Thiostrepton induced the synthesis of other proteins, some of which did not require tipA.
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autogenous transcriptional activation of a Thiostrepton induced gene in streptomyces lividans
The EMBO Journal, 1993Co-Authors: D J Holmes, J L Caso, Charles J ThompsonAbstract:Although the antibiotic Thiostrepton is best known as an inhibitor of protein synthesis, it also, at extremely low concentrations (< 10(-9) M), induces the expression of a regulon of unknown function in certain Streptomyces species. Here, we report the purification of a Streptomyces lividans Thiostrepton-induced transcriptional activator protein, TipAL, whose N-terminus is similar to a family of eubacterial regulatory proteins represented by MerR. TipAL was first purified from induced cultures of S.lividans as a factor which bound to and activated transcription from its own promoter. The tipAL gene was overexpressed in Escherichia coli and TipAL protein purified in a single step using a Thiostrepton affinity column. Thiostrepton enhanced binding of TipAL to the promoter and catalysed specific transcription in vitro. TipAS, a second gene product of the same open reading frame consisting of the C-terminal domain of TipAL, is apparently translated using its own in-frame initiation site. Since it is produced in large molar excess relative to TipAL after induction and also binds Thiostrepton, it may competitively modulate transcriptional activation.
Alain Guillot - One of the best experts on this subject based on the ideXlab platform.
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Thiostrepton tryptophan methyltransferase expands the chemistry of radical sam enzymes
Nature Chemical Biology, 2012Co-Authors: Alhosna Benjdia, Olivier Berteau, Stephane Pierre, Alain Guillot, Corine Sandstrom, Philippe LangellaAbstract:TsrM, a member of the radical SAM enzyme family, is shown to catalyze tryptophan methylation en route to Thiostrepton A with the help of a methylcobalamin cofactor and without generating the canonical 5-deoxyadenosyl radical.
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Thiostrepton tryptophan methyltransferase expands the chemistry of radical SAM enzymes
Nature Chemical Biology, 2012Co-Authors: Stephane Pierre, Alhosna Benjdia, Alain Guillot, Corine Sandstrom, Philippe Langella, Olivier BerteauAbstract:Methylation is among the most widespread chemical modifications encountered in biomolecules and has a pivotal role in many major biological processes. In the biosynthetic pathway of the antibiotic Thiostrepton A, we identified what is to our knowledge the first tryptophan methyltransferase. We show that it uses unprecedented chemistry to methylate inactivated sp(2)-hybridized carbon atoms, despite being predicted to be a radical SAM enzyme.
