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Hirota Fujiki - One of the best experts on this subject based on the ideXlab platform.
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Tumor necrosis factor-alpha, a new tumor promoter, engendered by biochemical studies of Okadaic Acid.
Journal of Biochemistry, 1994Co-Authors: Hirota Fujiki, Masami SuganumaAbstract:: Okadaic Acid is a potent tumor promoter on mouse skin and in rat glandular stomach, and an inhibitor of PP-1 and PP-2A. How Okadaic Acid biochemically induces tumor promotion in these tissues was reviewed. Okadaic Acid bound to a catalytic subunit of PP-1 and PP-2A and induced hyperphosphorylation of proteins, such as vimentin, cytokeratins, HSP 27, and tumor suppressor gene products. Since one of the Okadaic Acid class compounds, microcystin-LR, induced tumor promotion in rat liver, the Okadaic Acid pathway mediated through inhibition of PP-1 and PP-2A is seen to be a general biochemical process of tumor promotion in various organs. The biochemical mimicry of Okadaic Acid by TNF-alpha led us to find that TNF-alpha is an endogenous tumor promoter. The study of tumor promotion in two-stage carcinogenesis experiments with the Okadaic Acid class of compounds engendered a new tumor promoter applicable to human cancer development.
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tumor promotion by inhibitors of protein phosphatases 1 and 2a the Okadaic Acid class of compounds
Advances in Cancer Research, 1993Co-Authors: Hirota Fujiki, Masami SuganumaAbstract:Publisher Summary Tumor promotion by the Okadaic Acid class of compounds binds to the Okadaic Acid receptors protein phosphatases 1 and 2A (PP-1 and PP-2A), which inhibit their activities. It results in an increase of phosphorylation of proteins in the cells. This chapter reviews the Okadaic Acid class of tumor promoters and discusses the significance of inhibition of PP-1 and PP-2A—the Okadaic Acid pathway—in the study of tumor promotion. Two-stage carcinogenesis experiments with the Okadaic Acid class of compounds established a general mechanism of tumor promotion for various organs. Okadaic Acid was subjected to screening system for 12- O- tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, which consist of three successive tests. Okadaic Acid responded differently from TPA in the three tests. Thirty Okadaic Acid class compounds include four structurally different types—namely, Okadaic Acid, calyculin, microcystin, and tautomycin. The tumor promotion on mouse skin, rat glandular stomach, and the treatment of Okadaic Acid with teleocidin or TPA are also discussed in the chapter. Okadaic Acid and teleocidin showed about the same potencies for production of papillomas and carcinomas during tumor promotion. The structure, distribution, gene expression, and biochemical effects of Okadaic Acid class compounds are also summarized.
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Binding competition of Okadaic Acid derivatives to anti-Okadaic Acid antibody.
Toxicon, 1991Co-Authors: Jun Yatsunami, Hirota Fujiki, Masami Suganuma, Shinji Nishiwaki, Makoto Ojika, Kiyoyuki Yamada, Lawrence LevineAbstract:The serologic activities of structurally related Okadaic Acid derivatives have been determined. Binding of [3H]Okadaic Acid to rabbit anti-Okadaic Acid is inhibited with equal effectiveness by Okadaic Acid, dinophysistoxin-1, acanthifolicin, Okadaic Acid tetramethyl ether, and Okadaic Acid spiroketal II. Okadaic Acid spiroketal I, which lacks the F- and G-rings of Okadaic Acid, inhibits serologic binding about 60 times less effectively. The F- and G-rings of Okadaic Acid may comprise part of the epitopes recognized by some of the polyclonal antibodies.
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Promotion of BALB/3T3 cell transformation by the Okadaic Acid class of tumor promoters, Okadaic Acid and dinophysistoxin-1.
Japanese Journal of Cancer Research, 1991Co-Authors: Ayako Sakai, Hirota FujikiAbstract:Okadaic Acid and dinophysistoxin-1 are non-12-O-tetradecanoylphorbol-13-acetate (non-TPA)-type tumor promoters, which enhance chemically induced tumorigenesis on mouse skin through a different mechanism from that of TPA. In the present study, we examined the promoting effects of these Okadaic Acid class tumor promoters on a two-stage transformation using BALB/3T3 cells which was designed to simulate in vivo two-stage carcinogenesis. Cells were treated first with a low dose of the initiator 3-methylcholanthrene (MCA) and then with a test chemical. Okadaic Acid and dinophysistoxin-1 significantly enhanced the MCA-induced cell transformation. Okadaic Acid tetramethyl ether, an inactive compound, did not affect the transformation of MCA-treated cells. The Okadaic Acid class of tumor promoters failed to induce transformation without pretreatment by MCA. Okadaic Acid did not show initiating activity in the two-stage transformation assay in which cells were treated first with Okadaic Acid and then with TPA. These results indicate that this transformation assay with BALB/ 3T3 cells is useful to predict tumor-promoting activity of non-TPA-type as well as TPA-type tumor promoters, before long-term in vivo two-stage carcinogenesis experiments are carried out.
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Mechanisms of action of Okadaic Acid class tumor promoters on mouse skin.
Environmental Health Perspectives, 1991Co-Authors: Hirota Fujiki, Masami Suganuma, Shinji Nishiwaki, Seiji Yoshizawa, Boonsong Winyar, Takashi SugimuraAbstract:Okadaic Acid, dinophysistoxin-1 (35-methylOkadaic Acid), and calyculin A are the Okadaic Acid class of non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, which do not bind to the phorbol ester receptors in cell membranes or activate protein kinase C in vitro. They have potent tumor-promoting activities on mouse skin, as strong as TPA-type tumor promoters, such as TPA, teleocidin, and aplysiatoxin. DNA samples isolated from tumors induced by dimethylbenz(a)anthracene and each of the Okadaic Acid class tumor promoters had the same mutation at the second nucleotide of codon 61 (CAA to CTA) in the c-H-ras gene. Okadaic Acid receptors, protein phosphatases 1 and 2A, are present in the particulate as well as cytosolic fractions of various mouse tissues. The apparent activation of protein kinases by the Okadaic Acid class tumor promoters, after their incubation with {sup 32}P-ATP, protein kinases, and protein phosphatases, was observed. This activation was caused by inhibition of protein phosphatases 1 and 2A by the Okadaic Acid class tumor promoters. Treatment of primary human fibroblasts and human keratinocytes with the Okadaic Acid class tumor promoters induced the hyperphosphorylation of a 60-k-Da protein in nuclear and cytosolic fractions, due to the inhibition of protein phosphatases. The 60-kDa protein is a proteolytic fragmentmore » of nucleolin, a major nonhistone protein and is designated as N-60. The mechanisms of action of the Okadaic Acid class tumor promoters are discussed with emphasis on the inhibition of protein phosphatase activity.« less
Masami Suganuma - One of the best experts on this subject based on the ideXlab platform.
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Tumor necrosis factor-alpha, a new tumor promoter, engendered by biochemical studies of Okadaic Acid.
Journal of Biochemistry, 1994Co-Authors: Hirota Fujiki, Masami SuganumaAbstract:: Okadaic Acid is a potent tumor promoter on mouse skin and in rat glandular stomach, and an inhibitor of PP-1 and PP-2A. How Okadaic Acid biochemically induces tumor promotion in these tissues was reviewed. Okadaic Acid bound to a catalytic subunit of PP-1 and PP-2A and induced hyperphosphorylation of proteins, such as vimentin, cytokeratins, HSP 27, and tumor suppressor gene products. Since one of the Okadaic Acid class compounds, microcystin-LR, induced tumor promotion in rat liver, the Okadaic Acid pathway mediated through inhibition of PP-1 and PP-2A is seen to be a general biochemical process of tumor promotion in various organs. The biochemical mimicry of Okadaic Acid by TNF-alpha led us to find that TNF-alpha is an endogenous tumor promoter. The study of tumor promotion in two-stage carcinogenesis experiments with the Okadaic Acid class of compounds engendered a new tumor promoter applicable to human cancer development.
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tumor promotion by inhibitors of protein phosphatases 1 and 2a the Okadaic Acid class of compounds
Advances in Cancer Research, 1993Co-Authors: Hirota Fujiki, Masami SuganumaAbstract:Publisher Summary Tumor promotion by the Okadaic Acid class of compounds binds to the Okadaic Acid receptors protein phosphatases 1 and 2A (PP-1 and PP-2A), which inhibit their activities. It results in an increase of phosphorylation of proteins in the cells. This chapter reviews the Okadaic Acid class of tumor promoters and discusses the significance of inhibition of PP-1 and PP-2A—the Okadaic Acid pathway—in the study of tumor promotion. Two-stage carcinogenesis experiments with the Okadaic Acid class of compounds established a general mechanism of tumor promotion for various organs. Okadaic Acid was subjected to screening system for 12- O- tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, which consist of three successive tests. Okadaic Acid responded differently from TPA in the three tests. Thirty Okadaic Acid class compounds include four structurally different types—namely, Okadaic Acid, calyculin, microcystin, and tautomycin. The tumor promotion on mouse skin, rat glandular stomach, and the treatment of Okadaic Acid with teleocidin or TPA are also discussed in the chapter. Okadaic Acid and teleocidin showed about the same potencies for production of papillomas and carcinomas during tumor promotion. The structure, distribution, gene expression, and biochemical effects of Okadaic Acid class compounds are also summarized.
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Okadaic Acid is a potent angiogenesis inducer.
Japanese Journal of Cancer Research, 1992Co-Authors: Tsutomu Oikawa, Masami Suganuma, Hiromi Ashino-fuse, Mariko ShimamuraAbstract:: Okadaic Acid, which is a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoter and an inhibitor of protein phosphatases 1 and 2A, induced angiogenesis in the chorioallantoic membrane of the chick embryo. Its potent angiogenic activity was dose-dependent. The minimum effective dose was 5 fmol/egg and the effective dose for 50% induction was 90 fmol/egg. These results indicated that Okadaic Acid exhibits angiogenic activity one order of magnitude stronger than that of TPA (reported previously). Moreover, the time-course of angiogenesis induction by Okadaic Acid was much slower than that by TPA. The difference is consistent with the time-courses of other biochemical and biological activities and also various gene expressions induced by Okadaic Acid and TPA, indicating that the difference in the time-course is associated with their mechanisms of action. We conclude that Okadaic Acid induces angiogenesis through a different pathway than does TPA, indicating the existence of a new mechanism of angiogenesis induction.
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Binding competition of Okadaic Acid derivatives to anti-Okadaic Acid antibody.
Toxicon, 1991Co-Authors: Jun Yatsunami, Hirota Fujiki, Masami Suganuma, Shinji Nishiwaki, Makoto Ojika, Kiyoyuki Yamada, Lawrence LevineAbstract:The serologic activities of structurally related Okadaic Acid derivatives have been determined. Binding of [3H]Okadaic Acid to rabbit anti-Okadaic Acid is inhibited with equal effectiveness by Okadaic Acid, dinophysistoxin-1, acanthifolicin, Okadaic Acid tetramethyl ether, and Okadaic Acid spiroketal II. Okadaic Acid spiroketal I, which lacks the F- and G-rings of Okadaic Acid, inhibits serologic binding about 60 times less effectively. The F- and G-rings of Okadaic Acid may comprise part of the epitopes recognized by some of the polyclonal antibodies.
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Mechanisms of action of Okadaic Acid class tumor promoters on mouse skin.
Environmental Health Perspectives, 1991Co-Authors: Hirota Fujiki, Masami Suganuma, Shinji Nishiwaki, Seiji Yoshizawa, Boonsong Winyar, Takashi SugimuraAbstract:Okadaic Acid, dinophysistoxin-1 (35-methylOkadaic Acid), and calyculin A are the Okadaic Acid class of non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, which do not bind to the phorbol ester receptors in cell membranes or activate protein kinase C in vitro. They have potent tumor-promoting activities on mouse skin, as strong as TPA-type tumor promoters, such as TPA, teleocidin, and aplysiatoxin. DNA samples isolated from tumors induced by dimethylbenz(a)anthracene and each of the Okadaic Acid class tumor promoters had the same mutation at the second nucleotide of codon 61 (CAA to CTA) in the c-H-ras gene. Okadaic Acid receptors, protein phosphatases 1 and 2A, are present in the particulate as well as cytosolic fractions of various mouse tissues. The apparent activation of protein kinases by the Okadaic Acid class tumor promoters, after their incubation with {sup 32}P-ATP, protein kinases, and protein phosphatases, was observed. This activation was caused by inhibition of protein phosphatases 1 and 2A by the Okadaic Acid class tumor promoters. Treatment of primary human fibroblasts and human keratinocytes with the Okadaic Acid class tumor promoters induced the hyperphosphorylation of a 60-k-Da protein in nuclear and cytosolic fractions, due to the inhibition of protein phosphatases. The 60-kDa protein is a proteolytic fragmentmore » of nucleolin, a major nonhistone protein and is designated as N-60. The mechanisms of action of the Okadaic Acid class tumor promoters are discussed with emphasis on the inhibition of protein phosphatase activity.« less
C J Forsyth - One of the best experts on this subject based on the ideXlab platform.
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Okadaic Acid the archetypal serine threonine protein phosphatase inhibitor
Current Medicinal Chemistry, 2002Co-Authors: Amy B Dounay, C J ForsythAbstract:: As the first recognized member of the "Okadaic Acid class" of phosphatase inhibitors, the marine natural product Okadaic Acid is perhaps the most well-known member of a diverse array of secondary metabolites that have emerged as valuable probes for studying the roles of various cellular protein serine/threonine phosphatases. This review provides a historical perspective on the role that Okadaic Acid has played in stimulating a broad spectrum of modern scientific research as a result of the natural product's ability to bind to and inhibit important classes of protein serine / threonine phosphatases. The relationships between the structure and biological activities of Okadaic Acid are briefly reviewed, as well as the structural information regarding the particular cellular receptors protein phosphatases 1 (PP1) and 2A. Laboratory syntheses of Okadaic Acid and its analogs are thoroughly reviewed. Finally, an interpretation of the critical contacts observed between Okadaic Acid and PP1 by X-ray crystallography is provided, and specific molecular recognition hypotheses that are testable via the synthesis and assay of non-natural analogs of Okadaic Acid are suggested.
Patrick A Baeuerle - One of the best experts on this subject based on the ideXlab platform.
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induction of oxidative stress by Okadaic Acid is required for activation of transcription factor nf κb
Journal of Biological Chemistry, 1995Co-Authors: Kerstin N Schmidt, Brittamareen E Traenckner, Beate Meier, Patrick A BaeuerleAbstract:Abstract The widely used phosphatase 1 and 2A inhibitor Okadaic Acid is one of the many stimuli activating transcription factor NF-κB in cultured cells. Phosphorylation of IκB-α, one of NF-κB's inhibitory subunits, is a prerequisite for IκB degradation and the subsequent liberation of transcriptionally active NF-κB. This observation suggested that the phosphorylation status of IκB is influenced by an Okadaic Acid-sensitive phosphatase. In this study, we provide evidence that the effect of Okadaic Acid on NF-κB activation is indirect and dependent on the production of reactive oxygen intermediates rather than the inhibition of an IκB-α phosphatase. Okadaic Acid was found to be a strong inducer of cellular H2O2 and superoxide production in two distinct cell lines. The structurally unrelated phosphatase inhibitor calyculin A also induced oxidative stress. The delayed onset of reactive oxygen production in response to Okadaic Acid correlated with the delayed activation of NF-κB. Moreover, NF-κB induction was optimal at the same Okadaic Acid concentration that caused optimal H2O2 production. Both reactive oxygen intermediates production and NF-κB activation were inhibited by the antioxidant pyrrolidine dithiocarbamate and 8-(diethylamino)octyl-3,4,5-trimethyoxybenzoate, a Ca2+ chelator. Future experiments using phosphatase inhibitors in intact cells must consider that the compounds can act as strong inducers of oxidative stress, which provides one explanation for their tumor-promoting activity.
Amy B Dounay - One of the best experts on this subject based on the ideXlab platform.
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Okadaic Acid: The Archetypal Serine / Threonine Protein Phosphatase Inhibitor
Current Medicinal Chemistry, 2002Co-Authors: Amy B Dounay, Forsyth CjAbstract:: As the first recognized member of the "Okadaic Acid class" of phosphatase inhibitors, the marine natural product Okadaic Acid is perhaps the most well-known member of a diverse array of secondary metabolites that have emerged as valuable probes for studying the roles of various cellular protein serine/threonine phosphatases. This review provides a historical perspective on the role that Okadaic Acid has played in stimulating a broad spectrum of modern scientific research as a result of the natural product's ability to bind to and inhibit important classes of protein serine / threonine phosphatases. The relationships between the structure and biological activities of Okadaic Acid are briefly reviewed, as well as the structural information regarding the particular cellular receptors protein phosphatases 1 (PP1) and 2A. Laboratory syntheses of Okadaic Acid and its analogs are thoroughly reviewed. Finally, an interpretation of the critical contacts observed between Okadaic Acid and PP1 by X-ray crystallography is provided, and specific molecular recognition hypotheses that are testable via the synthesis and assay of non-natural analogs of Okadaic Acid are suggested.
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Okadaic Acid the archetypal serine threonine protein phosphatase inhibitor
Current Medicinal Chemistry, 2002Co-Authors: Amy B Dounay, C J ForsythAbstract:: As the first recognized member of the "Okadaic Acid class" of phosphatase inhibitors, the marine natural product Okadaic Acid is perhaps the most well-known member of a diverse array of secondary metabolites that have emerged as valuable probes for studying the roles of various cellular protein serine/threonine phosphatases. This review provides a historical perspective on the role that Okadaic Acid has played in stimulating a broad spectrum of modern scientific research as a result of the natural product's ability to bind to and inhibit important classes of protein serine / threonine phosphatases. The relationships between the structure and biological activities of Okadaic Acid are briefly reviewed, as well as the structural information regarding the particular cellular receptors protein phosphatases 1 (PP1) and 2A. Laboratory syntheses of Okadaic Acid and its analogs are thoroughly reviewed. Finally, an interpretation of the critical contacts observed between Okadaic Acid and PP1 by X-ray crystallography is provided, and specific molecular recognition hypotheses that are testable via the synthesis and assay of non-natural analogs of Okadaic Acid are suggested.
