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Ho Jeong Kwon - One of the best experts on this subject based on the ideXlab platform.
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association of sustained erk activity with integrin β3 induction during receptor activator of nuclear factor kappab ligand rankl directed osteoclast differentiation
Experimental Cell Research, 2003Co-Authors: Hong Hee Kim, Ho Jeong Kwon, Woon Jae Chung, Soo Woong Lee, Pah Jin Chung, Jae Won You, Sakae Tanaka, Zang Hee LeeAbstract:Osteoclast differentiation is a multi-step process that involves cell proliferation, commitment, and fusion. Some adhesion molecules, including integrin alphavbeta3, have been shown to have roles in osteoclast fusion. In the course of studying with pharmacologic agents known to inhibit protein tyrosine kinases of the Src family, we found that Radicicol increased cell fusion during receptor activator of nuclear factor kappaB ligand (RANKL)-driven differentiation of osteoclasts at concentrations far below the ones shown to inhibit its targets in previous studies. Treatments of low doses of Radicicol to RAW 264.7 cells that undergo osteoclastic differentiation in the presence of RANKL enhanced the RANKL-induced gene expression of integrin beta3 without any effect on the expression of integrin alphav, which was constitutively high. The cell surface level of integrin alphavbeta3 complexes was consequently augmented by Radicicol. In addition, sustained ERK and MEK activation was observed in cells treated with both Radicicol and RANKL. More importantly, modulation of ERK activity by the MEK inhibitor U0126 or the gene transduction of a constitutively active form of MEK resulted in a suppression and increment, respectively, of integrin beta3 induction by RANKL. Our data indicate that sustained ERK activity is associated with integrin beta3 induction and subsequent cell surface expression of the alphavbeta3 integrin complex, which may contribute to cell fusion during RANKL-directed osteoclastogenesis.
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Reduction of Hypoxia-Induced Transcription through the Repression of Hypoxia-Inducible Factor-1α/Aryl Hydrocarbon Receptor Nuclear Translocator DNA Binding by the 90-kDa Heat-Shock Protein Inhibitor Radicicol
Molecular pharmacology, 2002Co-Authors: Eunseon Hur, Ho Jeong Kwon, Hong Hee Kim, Su Mi Choi, Jin Hee Kim, Sujin Yim, Youngyeon Choi, Dae Kyong Kim, Mi Ock Lee, Hyunsung ParkAbstract:Under low oxygen tension, cells increase the transcription of specific genes involved in angiogenesis, erythropoiesis, and glycolysis. Hypoxia-induced gene expression depends primarily on stabilization of the α subunit of hypoxia-inducible factor-1 (HIF-1α), which acts as a heterodimeric trans-activator with the nuclear protein known as the aryl hydrocarbon receptor nuclear translocator (Arnt). The resulting heterodimer (HIF-1α/Arnt) interacts specifically with the hypoxia-responsive element (HRE), thereby increasing transcription of the genes under HRE control. Our results indicate that the 90-kDa heat-shock protein (Hsp90) inhibitor Radicicol reduces the hypoxia-induced expression of both endogenous vascular endothelial growth factor (VEGF) and HRE-driven reporter plasmids. Radicicol treatment (0.5 μg/ml) does not significantly change the stability of the HIF-1α protein and does not inhibit the nuclear localization of HIF-1α. However, this dose of Radicicol significantly reduces HRE binding by the HIF-1α/Arnt heterodimer. Our results, the first to show that Radicicol specifically inhibits the interaction between the HIF-1α/Arnt heterodimer and HRE, suggest that Hsp90 modulates the conformation of the HIF-1α/Arnt heterodimer, making it suitable for interaction with HRE. Furthermore, we demonstrate that Radicicol reduces hypoxia-induced VEGF expression to decrease hypoxia-induced angiogenesis.
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reduction of hypoxia induced transcription through the repression of hypoxia inducible factor 1α aryl hydrocarbon receptor nuclear translocator dna binding by the 90 kda heat shock protein inhibitor Radicicol
Molecular Pharmacology, 2002Co-Authors: Eunseon Hur, Ho Jeong Kwon, Hong Hee Kim, Su Mi Choi, Jin Hee Kim, Sujin Yim, Youngyeon Choi, Dae Kyong Kim, Mi Ock Lee, Hyunsung ParkAbstract:Under low oxygen tension, cells increase the transcription of specific genes involved in angiogenesis, erythropoiesis, and glycolysis. Hypoxia-induced gene expression depends primarily on stabilization of the α subunit of hypoxia-inducible factor-1 (HIF-1α), which acts as a heterodimeric trans-activator with the nuclear protein known as the aryl hydrocarbon receptor nuclear translocator (Arnt). The resulting heterodimer (HIF-1α/Arnt) interacts specifically with the hypoxia-responsive element (HRE), thereby increasing transcription of the genes under HRE control. Our results indicate that the 90-kDa heat-shock protein (Hsp90) inhibitor Radicicol reduces the hypoxia-induced expression of both endogenous vascular endothelial growth factor (VEGF) and HRE-driven reporter plasmids. Radicicol treatment (0.5 μg/ml) does not significantly change the stability of the HIF-1α protein and does not inhibit the nuclear localization of HIF-1α. However, this dose of Radicicol significantly reduces HRE binding by the HIF-1α/Arnt heterodimer. Our results, the first to show that Radicicol specifically inhibits the interaction between the HIF-1α/Arnt heterodimer and HRE, suggest that Hsp90 modulates the conformation of the HIF-1α/Arnt heterodimer, making it suitable for interaction with HRE. Furthermore, we demonstrate that Radicicol reduces hypoxia-induced VEGF expression to decrease hypoxia-induced angiogenesis.
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Radicicol represses the transcriptional function of the estrogen receptor by suppressing the stabilization of the receptor by heat shock protein 90.
Molecular and Cellular Endocrinology, 2001Co-Authors: Mi Ock Lee, Ho Jeong Kwon, Kim Eun-o, Youngmi Kim, Hyo Jin Kang, Heonjoong Kang, Jong Eun LeeAbstract:Abstract The estrogen receptor (ER) is a hormone-dependent transcription factor that belongs to the steroid/thyroid hormone receptor superfamily. Since the ER contributes to development and progression in human breast cancer, a number of studies have explored ways to inactivate this receptor. Previous studies have suggested that the 90-kDa heat shock protein (Hsp90) interacts with the ER, thus stabilizing the receptor in an inactive state. Here, we report that Radicicol, an Hsp90-specific inhibitor, repressed estrogen-dependent transactivation of the ER as measured by pS2 gene transcription and a reporter gene encoding an estrogen-responsive element. Furthermore, we showed that Radicicol induced rapid degradation of ERα, while the amount of ubiquitinated ERα was increased. A proteasome inhibitor, LLnL, almost completely abrogated the Radicicol-induced decrease in expression level, as well as in transcriptional activity of ERα. These results suggest that Radicicol disrupts the ER-Hsp90 heterodimeric complex, thereby generating ERα that is susceptible to ubiquitin/proteasome-induced degradation.
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Radicicol binding to swo1 hsp90 and inhibition of growth of specific temperature sensitive cell cycle mutants of fission yeast
Bioscience Biotechnology and Biochemistry, 2001Co-Authors: Ken Ishigami, Koji Kasahara, Takeshi Kitahara, Minoru Yoshida, Teruhiko Beppu, Ho Jeong Kwon, Sueharu HorinouchiAbstract:A panel screening using cdc mutants of Schizosaccharomyces pombe identified Radicicol as a potent growth inhibitor of certain mutants at the permissive temperature. The strains sensitive to Radicicol were cdc7, cdc11, and cdc14, all of which are defective in early septum formation. Cytokinesis but not nuclear division of these mutants was inhibited by Radicicol, but that of cells with the wild-type background was not. A biologically active derivative of Radicicol with a biotin moiety at the C-11 position bound Swo1, an Hsp90 homologue in S. pombe. Increased Swo1 expresion partially suppressed Radicicol sensitivity of cdc14 and almost completely rescued morphological abnormalities in cdc14 and cdc7 cells induced by Radicicol at the permissive temperature. On the other hand, the increased Swo1 expression did not restore septum formation at the nonpermissive temperature. These results suggest that Swo1, as a molecular chaperone, plays a role in stabilizing these temperature-sensitive proteins at the permissi...
Sueharu Horinouchi - One of the best experts on this subject based on the ideXlab platform.
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Radicicol binding to swo1 hsp90 and inhibition of growth of specific temperature sensitive cell cycle mutants of fission yeast
Bioscience Biotechnology and Biochemistry, 2001Co-Authors: Ken Ishigami, Koji Kasahara, Takeshi Kitahara, Minoru Yoshida, Teruhiko Beppu, Ho Jeong Kwon, Sueharu HorinouchiAbstract:A panel screening using cdc mutants of Schizosaccharomyces pombe identified Radicicol as a potent growth inhibitor of certain mutants at the permissive temperature. The strains sensitive to Radicicol were cdc7, cdc11, and cdc14, all of which are defective in early septum formation. Cytokinesis but not nuclear division of these mutants was inhibited by Radicicol, but that of cells with the wild-type background was not. A biologically active derivative of Radicicol with a biotin moiety at the C-11 position bound Swo1, an Hsp90 homologue in S. pombe. Increased Swo1 expresion partially suppressed Radicicol sensitivity of cdc14 and almost completely rescued morphological abnormalities in cdc14 and cdc7 cells induced by Radicicol at the permissive temperature. On the other hand, the increased Swo1 expression did not restore septum formation at the nonpermissive temperature. These results suggest that Swo1, as a molecular chaperone, plays a role in stabilizing these temperature-sensitive proteins at the permissi...
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Radicicol Binding to Swo1/Hsp90 and Inhibition of Growth of Specific Temperature-sensitive Cell Cycle Mutants of Fission Yeast
Bioscience biotechnology and biochemistry, 2001Co-Authors: Koji Kasahara, Ken Ishigami, Takeshi Kitahara, Minoru Yoshida, Teruhiko Beppu, Ho Jeong Kwon, Sueharu HorinouchiAbstract:A panel screening using cdc mutants of Schizosaccharomyces pombe identified Radicicol as a potent growth inhibitor of certain mutants at the permissive temperature. The strains sensitive to Radicicol were cdc7, cdc11, and cdc14, all of which are defective in early septum formation. Cytokinesis but not nuclear division of these mutants was inhibited by Radicicol, but that of cells with the wild-type background was not. A biologically active derivative of Radicicol with a biotin moiety at the C-11 position bound Swo1, an Hsp90 homologue in S. pombe. Increased Swo1 expresion partially suppressed Radicicol sensitivity of cdc14 and almost completely rescued morphological abnormalities in cdc14 and cdc7 cells induced by Radicicol at the permissive temperature. On the other hand, the increased Swo1 expression did not restore septum formation at the nonpermissive temperature. These results suggest that Swo1, as a molecular chaperone, plays a role in stabilizing these temperature-sensitive proteins at the permissi...
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Radicicol binds and inhibits mammalian atp citrate lyase
Journal of Biological Chemistry, 2000Co-Authors: Se Won Ki, Ken Ishigami, Koji Kasahara, Takeshi Kitahara, Minoru Yoshida, Sueharu HorinouchiAbstract:Abstract Six different biotinylated Radicicol derivatives were synthesized as affinity probes for identification of cellular Radicicol-binding proteins. Derivatives biotinylated at the C-17 (BR-1) and C-11 (BR-6) positions retained the activity of morphological reversion in v-src-transformed 3Y1 fibroblasts. Two Radicicol-binding proteins, 120 and 90-kDa in size, were detected in HeLa cell extracts by employing BR-1 and BR-6, respectively. The 90-kDa protein bound to BR-6 was identified to be Hsp90 by immunoblotting. The 120-kDa protein bound to BR-1 was purified from rabbit reticulocyte lysate, and its internal amino acid sequence was identical to that of human and rat ATP citrate lyase. The identity of the 120-kDa protein as ATP citrate lyase was confirmed by immunoblotting. Interaction between BR-1 and ATP citrate lyase was blocked by Radicicol but not by herbimycin A that interacts with Hsp90. These results suggest that Radicicol binds the two proteins through different molecular portions of its structure. BR-1-bound ATP citrate lyase isolated from rabbit reticulocyte lysate showed no enzymatic activity. The activity of rat liver ATP citrate lyase was inhibited by Radicicol and BR-1 but not by BR-6. Kinetic analysis demonstrated that Radicicol was a non-competitive inhibitor of ATP citrate lyase withK i values for citrate and ATP of 13 and 7 μm, respectively.
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identification of Radicicol as an inhibitor of in vivo ras raf interaction with the yeast two hybrid screening system
The Journal of Antibiotics, 1998Co-Authors: Koji Kasahara, Minoru Yoshida, Ho Jeong Kwon, Jun Eishima, Kazutoh Takesako, Jonathan A. Cooper, Sueharu HorinouchiAbstract:Activation of cytoplasmic serine/threonine kinase Raf-1, an important effector of Ras, requires direct binding to Ras. The yeast two-hybrid screening system used for identification of inhibitors of Ras/Raf-1 interaction showed Radicicol to be an inhibitor. Radicicol has been shown to induce morphological reversion of transformed cells. Immunoprecipitation with an anti-Ras antibody revealed that the in vivo Ras/Raf-1 binding in v-Ha-ras-transformed cells was also blocked by low concentrations of Radicicol (0.1∼1 μg/ml), while degradation of Raf-1 was induced at concentrations higher than 2 μg/ml. However, in vitro binding of glutathion S-transferase-fused Ras to a maltose binding protein-fused RIP3 containing the Ras-binding domain (RBD) of Raf-1 was not inhibited by Radicicol. Similar two-hybrid assays with several truncated forms of Raf-1 showed that both the conserved serine/threonine-rich domain (CR2) and the C-terminal protein kinase domain (CR3) were required for the full inhibition by Radicicol. These results suggest that Radicicol interacts directly or indirectly with the region except with RBD of Raf-1, thereby inhibiting a conformational change of Raf-1 prerequisite for binding to Ras.
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Identification of Radicicol as an Inhibitor of In Vivo Ras/Raf Interaction with the Yeast Two-hybrid Screening System
The Journal of antibiotics, 1998Co-Authors: Koji Kasahara, Minoru Yoshida, Ho Jeong Kwon, Jun Eishima, Kazutoh Takesako, Jonathan A. Cooper, Sueharu HorinouchiAbstract:Activation of cytoplasmic serine/threonine kinase Raf-1, an important effector of Ras, requires direct binding to Ras. The yeast two-hybrid screening system used for identification of inhibitors of Ras/Raf-1 interaction showed Radicicol to be an inhibitor. Radicicol has been shown to induce morphological reversion of transformed cells. Immunoprecipitation with an anti-Ras antibody revealed that the in vivo Ras/Raf-1 binding in v-Ha-ras-transformed cells was also blocked by low concentrations of Radicicol (0.1∼1 μg/ml), while degradation of Raf-1 was induced at concentrations higher than 2 μg/ml. However, in vitro binding of glutathion S-transferase-fused Ras to a maltose binding protein-fused RIP3 containing the Ras-binding domain (RBD) of Raf-1 was not inhibited by Radicicol. Similar two-hybrid assays with several truncated forms of Raf-1 showed that both the conserved serine/threonine-rich domain (CR2) and the C-terminal protein kinase domain (CR3) were required for the full inhibition by Radicicol. These results suggest that Radicicol interacts directly or indirectly with the region except with RBD of Raf-1, thereby inhibiting a conformational change of Raf-1 prerequisite for binding to Ras.
Minoru Yoshida - One of the best experts on this subject based on the ideXlab platform.
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Radicicol potentiates neurotrophin-mediated neurite outgrowth and survival of cultured sensory neurons from chick embryo.
Journal of neurochemistry, 2002Co-Authors: Mamoru Sano, Minoru Yoshida, Shigeyuki Fukui, Satoko KitajimaAbstract:Abstract: Radicicol, an antifungal antibiotic with markedly low toxicity, is a potent inhibitor of the Src family of protein tyrosine kinases and causes morphological reversion of v-src-transformed fibroblasts. Recently, this antibiotic was also found to inhibit Raf kinase. In the present study, we found that nanomolar concentrations of Radicicol (10 ng/ml) enhanced the survival and neurite outgrowth of neurons from embryonic chick dorsal root ganglia (DRGs) and sympathetic ganglia. It potentiated the trophic effects of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 on the cultured DRG neurons. This concentration of Radicicol did not alter the tyrosine phosphorylation of Trk receptors or the activity of mitogen-activated protein (MAP) kinases. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (P13-kinase), did not inhibit Radicicol, excluding the involvement of P13-kinase in the Radicicol-dependent trophic actions. These results suggest that Radicicol mediates neuronal growth presumably via a mechanism not involving the activation of Trk receptors, MAP kinase, or P13-kinase.
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Radicicol binding to swo1 hsp90 and inhibition of growth of specific temperature sensitive cell cycle mutants of fission yeast
Bioscience Biotechnology and Biochemistry, 2001Co-Authors: Ken Ishigami, Koji Kasahara, Takeshi Kitahara, Minoru Yoshida, Teruhiko Beppu, Ho Jeong Kwon, Sueharu HorinouchiAbstract:A panel screening using cdc mutants of Schizosaccharomyces pombe identified Radicicol as a potent growth inhibitor of certain mutants at the permissive temperature. The strains sensitive to Radicicol were cdc7, cdc11, and cdc14, all of which are defective in early septum formation. Cytokinesis but not nuclear division of these mutants was inhibited by Radicicol, but that of cells with the wild-type background was not. A biologically active derivative of Radicicol with a biotin moiety at the C-11 position bound Swo1, an Hsp90 homologue in S. pombe. Increased Swo1 expresion partially suppressed Radicicol sensitivity of cdc14 and almost completely rescued morphological abnormalities in cdc14 and cdc7 cells induced by Radicicol at the permissive temperature. On the other hand, the increased Swo1 expression did not restore septum formation at the nonpermissive temperature. These results suggest that Swo1, as a molecular chaperone, plays a role in stabilizing these temperature-sensitive proteins at the permissi...
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Radicicol Binding to Swo1/Hsp90 and Inhibition of Growth of Specific Temperature-sensitive Cell Cycle Mutants of Fission Yeast
Bioscience biotechnology and biochemistry, 2001Co-Authors: Koji Kasahara, Ken Ishigami, Takeshi Kitahara, Minoru Yoshida, Teruhiko Beppu, Ho Jeong Kwon, Sueharu HorinouchiAbstract:A panel screening using cdc mutants of Schizosaccharomyces pombe identified Radicicol as a potent growth inhibitor of certain mutants at the permissive temperature. The strains sensitive to Radicicol were cdc7, cdc11, and cdc14, all of which are defective in early septum formation. Cytokinesis but not nuclear division of these mutants was inhibited by Radicicol, but that of cells with the wild-type background was not. A biologically active derivative of Radicicol with a biotin moiety at the C-11 position bound Swo1, an Hsp90 homologue in S. pombe. Increased Swo1 expresion partially suppressed Radicicol sensitivity of cdc14 and almost completely rescued morphological abnormalities in cdc14 and cdc7 cells induced by Radicicol at the permissive temperature. On the other hand, the increased Swo1 expression did not restore septum formation at the nonpermissive temperature. These results suggest that Swo1, as a molecular chaperone, plays a role in stabilizing these temperature-sensitive proteins at the permissi...
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Radicicol binds and inhibits mammalian atp citrate lyase
Journal of Biological Chemistry, 2000Co-Authors: Se Won Ki, Ken Ishigami, Koji Kasahara, Takeshi Kitahara, Minoru Yoshida, Sueharu HorinouchiAbstract:Abstract Six different biotinylated Radicicol derivatives were synthesized as affinity probes for identification of cellular Radicicol-binding proteins. Derivatives biotinylated at the C-17 (BR-1) and C-11 (BR-6) positions retained the activity of morphological reversion in v-src-transformed 3Y1 fibroblasts. Two Radicicol-binding proteins, 120 and 90-kDa in size, were detected in HeLa cell extracts by employing BR-1 and BR-6, respectively. The 90-kDa protein bound to BR-6 was identified to be Hsp90 by immunoblotting. The 120-kDa protein bound to BR-1 was purified from rabbit reticulocyte lysate, and its internal amino acid sequence was identical to that of human and rat ATP citrate lyase. The identity of the 120-kDa protein as ATP citrate lyase was confirmed by immunoblotting. Interaction between BR-1 and ATP citrate lyase was blocked by Radicicol but not by herbimycin A that interacts with Hsp90. These results suggest that Radicicol binds the two proteins through different molecular portions of its structure. BR-1-bound ATP citrate lyase isolated from rabbit reticulocyte lysate showed no enzymatic activity. The activity of rat liver ATP citrate lyase was inhibited by Radicicol and BR-1 but not by BR-6. Kinetic analysis demonstrated that Radicicol was a non-competitive inhibitor of ATP citrate lyase withK i values for citrate and ATP of 13 and 7 μm, respectively.
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identification of Radicicol as an inhibitor of in vivo ras raf interaction with the yeast two hybrid screening system
The Journal of Antibiotics, 1998Co-Authors: Koji Kasahara, Minoru Yoshida, Ho Jeong Kwon, Jun Eishima, Kazutoh Takesako, Jonathan A. Cooper, Sueharu HorinouchiAbstract:Activation of cytoplasmic serine/threonine kinase Raf-1, an important effector of Ras, requires direct binding to Ras. The yeast two-hybrid screening system used for identification of inhibitors of Ras/Raf-1 interaction showed Radicicol to be an inhibitor. Radicicol has been shown to induce morphological reversion of transformed cells. Immunoprecipitation with an anti-Ras antibody revealed that the in vivo Ras/Raf-1 binding in v-Ha-ras-transformed cells was also blocked by low concentrations of Radicicol (0.1∼1 μg/ml), while degradation of Raf-1 was induced at concentrations higher than 2 μg/ml. However, in vitro binding of glutathion S-transferase-fused Ras to a maltose binding protein-fused RIP3 containing the Ras-binding domain (RBD) of Raf-1 was not inhibited by Radicicol. Similar two-hybrid assays with several truncated forms of Raf-1 showed that both the conserved serine/threonine-rich domain (CR2) and the C-terminal protein kinase domain (CR3) were required for the full inhibition by Radicicol. These results suggest that Radicicol interacts directly or indirectly with the region except with RBD of Raf-1, thereby inhibiting a conformational change of Raf-1 prerequisite for binding to Ras.
Teruhiko Beppu - One of the best experts on this subject based on the ideXlab platform.
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Radicicol binding to swo1 hsp90 and inhibition of growth of specific temperature sensitive cell cycle mutants of fission yeast
Bioscience Biotechnology and Biochemistry, 2001Co-Authors: Ken Ishigami, Koji Kasahara, Takeshi Kitahara, Minoru Yoshida, Teruhiko Beppu, Ho Jeong Kwon, Sueharu HorinouchiAbstract:A panel screening using cdc mutants of Schizosaccharomyces pombe identified Radicicol as a potent growth inhibitor of certain mutants at the permissive temperature. The strains sensitive to Radicicol were cdc7, cdc11, and cdc14, all of which are defective in early septum formation. Cytokinesis but not nuclear division of these mutants was inhibited by Radicicol, but that of cells with the wild-type background was not. A biologically active derivative of Radicicol with a biotin moiety at the C-11 position bound Swo1, an Hsp90 homologue in S. pombe. Increased Swo1 expresion partially suppressed Radicicol sensitivity of cdc14 and almost completely rescued morphological abnormalities in cdc14 and cdc7 cells induced by Radicicol at the permissive temperature. On the other hand, the increased Swo1 expression did not restore septum formation at the nonpermissive temperature. These results suggest that Swo1, as a molecular chaperone, plays a role in stabilizing these temperature-sensitive proteins at the permissi...
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Radicicol Binding to Swo1/Hsp90 and Inhibition of Growth of Specific Temperature-sensitive Cell Cycle Mutants of Fission Yeast
Bioscience biotechnology and biochemistry, 2001Co-Authors: Koji Kasahara, Ken Ishigami, Takeshi Kitahara, Minoru Yoshida, Teruhiko Beppu, Ho Jeong Kwon, Sueharu HorinouchiAbstract:A panel screening using cdc mutants of Schizosaccharomyces pombe identified Radicicol as a potent growth inhibitor of certain mutants at the permissive temperature. The strains sensitive to Radicicol were cdc7, cdc11, and cdc14, all of which are defective in early septum formation. Cytokinesis but not nuclear division of these mutants was inhibited by Radicicol, but that of cells with the wild-type background was not. A biologically active derivative of Radicicol with a biotin moiety at the C-11 position bound Swo1, an Hsp90 homologue in S. pombe. Increased Swo1 expresion partially suppressed Radicicol sensitivity of cdc14 and almost completely rescued morphological abnormalities in cdc14 and cdc7 cells induced by Radicicol at the permissive temperature. On the other hand, the increased Swo1 expression did not restore septum formation at the nonpermissive temperature. These results suggest that Swo1, as a molecular chaperone, plays a role in stabilizing these temperature-sensitive proteins at the permissi...
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Suppression of morphological transformation by Radicicol is accompanied by enhanced gelsolin expression
Oncogene, 1997Co-Authors: Ho Jeong Kwon, Minoru Yoshida, Teruhiko Beppu, Rie Nagaoka, Takashi Obinata, Sueharu HorinouchiAbstract:Radicicol, an inhibitor of Src-family protein-tyrosine kinases, causes morphological reversion of v-src- and v-Ha-ras-transformed fibroblasts and arrest of the cell cycle at both the G1 and the G2 phases. Radicicol was found to inhibit the growth of several other oncogene-transformed cell lines and human carcinoma cell lines and to revert their cell morphology to be flat. In the Radicicol-treated flat cells, actin stress fiber bundles were reorganized. Since this effect of Radicicol on these cell lines was inhibited by cycloheximide, de novo protein synthesis is required for the morphological reversion. Screening of cellular proteins enhanced in response to Radicicol by two-dimensional gel electrophoresis suggested that the amount of gelsolin, an actin regulatory protein, was distinctly increased upon Radicicol treatment. Western blot and Northern blot analyses showed that Radicicol enhanced transcription of the gelsolin gene in human carcinoma cell lines, as a result of which the amount of gelsolin was increased several folds. Injection with an anti-gelsolin antibody into cells and successive treatment with Radicicol resulted in approximately 80% reduction of the number of flat cells with stress fibers in comparison with controls treated with an irrelevant antibody. These results show that elevated expression of gelsolin is associated, at least in part, with the suppression of transformation and the restoration of actin stress fibers in human carcinoma cells by Radicicol.
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Radicicol, a protein tyrosine kinase inhibitor, suppresses the expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide and in experimental glomerulonephritis
The Journal of biological chemistry, 1995Co-Authors: Prithiva Chanmugam, Lili Feng, Shuenn Liou, Byeong C. Jang, Mary D. Boudreau, Jong H. Lee, Ho J. Kwon, Teruhiko Beppu, Minoru YoshidaAbstract:Abstract Two isoforms of cyclooxygenase (COX) have been identified in eukaryotic cells: a constitutively expressed COX-1 and mitogen-inducible COX-2, which is selectively expressed in response to various inflammatory stimuli. Thus, COX-2 instead of COX-1 is implicated to produce prostanoids mediating inflammatory responses. Major efforts have been focused on identifying nonsteroidal anti-inflammatory drugs (NSAIDS) which can selectively inhibit the enzyme activity of COX-2. Such NSAIDS would be more desirable anti-inflammatory agents in comparison to NSAIDS which inhibit both COX-1 and COX-2. Other than glucocorticoids, pharmacological agents which can selectively suppress the expression of COX-2 without affecting that of COX-1 have not been identified. We report here that Radicicol, a fungal antibiotic, is a potent protein tyrosine kinase inhibitor, and that it inhibits the expression of COX-2 without affecting COX-1 expression in lipopolysaccharide (LPS)-stimulated macrophages with the IC50 value of 27 nM. Radicicol inhibited tyrosine phosphorylation of p53/56lyn, a Src family tyrosine kinase and one of the major tyrosine-phosphorylated proteins in LPS-stimulated macrophages. Radicicol also inhibited COX-2 expression in vivo in glomeruli of rats with experimental glomerulonephritis induced by the anti-glomerular basement membrane antibodies, in which COX-2 expression is known to be enhanced. The enzyme activity of COX-1 or COX-2 was not affected by Radicicol in macrophages. Radicicol also suppressed the COX-2 expression induced by IL-1β in rat smooth muscle cells. Other protein tyrosine kinase inhibitors suppressed the LPS-induced COX-2 expression in macrophages but at much higher concentrations than needed for Radicicol. Radicicol did not inhibit the COX-2 expression induced by phorbol 12-myristate 13-acetate in macrophages. These results suggest that the activation of tyrosine-specific protein kinases is the proximal obligatory step in the LPS-induced signal transduction pathway leading to the induction of COX-2 expression in macrophages. The magnitude of the inhibition of COX-2 protein synthesis by Radicicol was much greater than that of the steady state levels of COX-2 mRNA. These results suggest that Radicicol inhibits COX-2 expression mainly at post-transcriptional steps.
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Morphology of ras-transformed cells becomes apparently normal again with tyrosine kinase inhibitors without a decrease in the ras-GTP complex.
Journal of biochemistry, 1995Co-Authors: Ho Jeong Kwon, Minoru Yoshida, Teruhiko Beppu, Kenkoh Muroya, Seisuke Hattori, Eisuke Nishida, Yasuhisa Fukui, Sueharu HorinouchiAbstract:Radicicol, an inhibitor of protein-tyrosine kinase, was found to cause morphological reversion of v-Ha-ras-transformed NIH3T3 fibroblasts and T24 human urinary bladder carcinoma cells that contain an activated ras mutation. The network of actin stress fibers was restored during the treatment with Radicicol. A similar morphological change was observed with another protein-tyrosine kinase inhibitor, herbimycin A. Radicicol did not cause any changes in the proportion of the active GTP binding form of p21ras or its subcellular localization. These results rule out the possibility that the morphological reversion by Radicicol is due to direct or indirect inhibition of the p21ras function. Cycloheximide and actinomycin D inhibited the morphological change by Radicicol, suggesting that the induced transcription of a gene(s) followed by de novo protein synthesis is required for suppression of the transformed phenotype in ras-transformed cells by tyrosine kinase inhibitors.
Akira Kawashima - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and structure-activity relationships of Radicicol derivatives and WNT-5A expression inhibitory activity.
Bioorganic & medicinal chemistry, 2009Co-Authors: Hideki Shinonaga, Akiko Ikeda, Mari Aoki, Natsuko Fujimoto, Toshiya Noguchi, Akira KawashimaAbstract:WNT-5A, a secretory glycoprotein, is related to the proliferation of dermal papilla cells. To develop a hair-growth stimulant, we have been searching for inhibitors of WNT-5A expression. We identified Radicicol (1) as an active compound, and synthesized several Radicicol derivatives. Among them, 6,7-dihydro-10α-hydroxy Radicicol (31) was found to function as a new potent WNT-5A expression inhibitor with relatively low toxicity and excellent stability.
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pochonins k p new Radicicol analogues from pochonia chlamydosporia var chlamydosporia and their wnt 5a expression inhibitory activities
Tetrahedron, 2009Co-Authors: Hideki Shinonaga, Yoji Kawamura, Akiko Ikeda, Mari Aoki, Noriyoshi Sakai, Natsuko Fujimoto, Akira KawashimaAbstract:Abstract WNT-5A, a secretory glycoprotein, is related to the proliferation of dermal papilla cells. To develop a hair-growth stimulant, we have been searching for an inhibitor of WNT-5A expression, and have identified an active compound, Radicicol ( 1 ), and isolated six new Radicicol analogues, pochonins K–P ( 2 – 7 ), together with ten known Radicicol analogues, including monorden analogue-1 ( 8 ), pochonin E ( 9 ), and pochonin F ( 10 ), from a culture broth of the fungus Pochonia chlamydosporia TF-0480. This report describes the structural elucidation of 2 – 7 , determination of the stereochemistries of 8 – 10 , and their biological activities against WNT-5A.
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Pochonins K–P: new Radicicol analogues from Pochonia chlamydosporia var. chlamydosporia and their WNT-5A expression inhibitory activities
Tetrahedron, 2009Co-Authors: Hideki Shinonaga, Yoji Kawamura, Akiko Ikeda, Mari Aoki, Noriyoshi Sakai, Natsuko Fujimoto, Akira KawashimaAbstract:Abstract WNT-5A, a secretory glycoprotein, is related to the proliferation of dermal papilla cells. To develop a hair-growth stimulant, we have been searching for an inhibitor of WNT-5A expression, and have identified an active compound, Radicicol ( 1 ), and isolated six new Radicicol analogues, pochonins K–P ( 2 – 7 ), together with ten known Radicicol analogues, including monorden analogue-1 ( 8 ), pochonin E ( 9 ), and pochonin F ( 10 ), from a culture broth of the fungus Pochonia chlamydosporia TF-0480. This report describes the structural elucidation of 2 – 7 , determination of the stereochemistries of 8 – 10 , and their biological activities against WNT-5A.
