Trichostatin C, a New Inducer of Differentiation of Friend Leukemic Cells

Yoshida, Minoru; Iwamoto, Yasushi; Uozumi, Tohru; Beppu, Teruhiko

doi:10.1080/00021369.1985.10866766

Cited by 6 publications

(7 citation statements)

References 2 publications

(2 reference statements)

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“…of the acetylatable N-terminal core histone lysines is similarly nonlethal (Megee et al, 1990;Durrin et al, 1991;Mann and Grunstein, 1992). lnhibition of HD with trichostatin and/or trapoxin causes detransformation of sis-oncogene-transformed human cells (Yoshida and Sugita, 1992), induces differentiation of leukemic cells (Yoshida et al, 1985), arrests the cell cycle of rat fibroblasts in G, and G P (Yoshida and Beppu, 1988), and blocks starfish development at the early gastrula stage (Ikegami et al, 1993); in none of these systems does trichostatin or Aeo-containing cyclic peptides cause cell death.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Maize Histone Deacetylases by HC Toxin, the Host-Selective Toxin of Cochliobolus carbonum

Brosch¹,

Ransom²,

Lechner³

et al. 1995

The Plant Cell

101

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HC toxin, the host-selective toxin of the maize pathogen Cochliobolus carbonum, inhibited maize histone deacetylase (HD) at 2 microM. Chlamydocin, a related cyclic tetrapeptide, also inhibited HD activity. The toxins did not affect histone acetyltransferases. After partial purification of histone deacetylases HD1-A, HD1-B, and HD2 from germinating maize embryos, we demonstrated that the different enzymes were similarly inhibited by the toxins. Inhibitory activities were reversibly eliminated by treating toxins with 2-mercaptoethanol, presumably by modifying the carbonyl group of the epoxide-containing amino acid Aeo (2-amino-9,10-epoxy-8-oxodecanoic acid). Kinetic studies revealed that inhibition of HD was of the uncompetitive type and reversible. HC toxin, in which the epoxide group had been hydrolyzed, completely lost its inhibitory activity; when the carbonyl group of Aeo had been reduced to the corresponding alcohol, the modified toxin was less active than native toxin. In vivo treatment of embryos with HC toxin caused the accumulation of highly acetylated histone H4 subspecies and elevated acetate incorporation into H4 in susceptible-genotype embryos but not in the resistant genotype. HDs from chicken and the myxomycete Physarum polycephalum were also inhibited, indicating that the host selectivity of HC toxin is not determined by its inhibitory effect on HD. Consistent with these results, we propose a model in which HC toxin promotes the establishment of pathogenic compatibility between C. carbonum and maize by interfering with reversible histone acetylation, which is implicated in the control of fundamental cellular processes, such as chromatin structure, cell cycle progression, and gene expression.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Maize Histone Deacetylases by HC Toxin, the Host-Selective Toxin of Cochliobolus carbonum

Brosch¹,

Ransom²,

Lechner³

et al. 1995

The Plant Cell

101

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“…22 ) TSA, which had been isolated from a Streptomyces strain as an antifungal antibiotic 23 ) was rediscovered as a powerful inducer of murine erythroleukemia cell differentiation. 24 , 25 ) TSA inhibited the activity of partially purified HDACs with a low nanomolar inhibition constant. TSA has a hydroxamic acid group, which can chelate a metal ion, suggesting that HDACs are metal-containing enzymes.…”

Section: Discovery Of Deacetylases and Their Inhibitorsmentioning

confidence: 99%

Chemical and structural biology of protein lysine deacetylases

Yoshida

Kudo

Kosono

et al. 2017

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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Histone acetylation is a reversible posttranslational modification that plays a fundamental role in regulating eukaryotic gene expression and chromatin structure/function. Key enzymes for removing acetyl groups from histones are metal (zinc)-dependent and NAD+-dependent histone deacetylases (HDACs). The molecular function of HDACs have been extensively characterized by various approaches including chemical, molecular, and structural biology, which demonstrated that HDACs regulate cell proliferation, differentiation, and metabolic homeostasis, and that their alterations are deeply involved in various human disorders including cancer. Notably, drug discovery efforts have achieved success in developing HDAC-targeting therapeutics for treatment of several cancers. However, recent advancements in proteomics technology have revealed much broader aspects of HDACs beyond gene expression control. Not only histones but also a large number of cellular proteins are subject to acetylation by histone acetyltransferases (HATs) and deacetylation by HDACs. Furthermore, some of their structures can flexibly accept and hydrolyze other acyl groups on protein lysine residues. This review mainly focuses on structural aspects of HDAC enzymatic activity regulated by interaction with substrates, co-factors, small molecule inhibitors, and activators.

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“…Trichostatin A, along with its fermentation congeners trichostatin B ((TSA) 3 •Fe, not shown) and trichostatic acid (5), are fungal metabolites produced by Streptomyces hygroscopicus [33]. Although these compounds were originally isolated in 1976, the demonstration that TSA acts as a potent differentiation inducer in leukemia models was not recognized for nearly a decade [34][35][36]. While TSA is quite potent, trichostatic acid fails to display useful biological activity in these assays.…”

Section: Hdac Enzyme X-ray Crystallo-graphic Studiesmentioning

confidence: 99%

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Meinke¹,

Liberator²

2001

CMC

108

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Histone deacetylase (HDAC) and histone acetyltransferase (HAT) are enzymes that influence transcription by selectively deacetylating or acetylating the eta-amino groups of lysines located near the amino termini of core histone proteins. It is well-established that in transcriptionally active chromatin, histones generally are hyperacetylated and, conversely, hypoacetylated histones are coincident with silenced chromatin. Revived interest in these enzymatic pathways and how they modulate eukaryotic transcription has led to the identification of multiple cofactors whose complex interplay with HDAC affects gene expression. Concurrent with these discoveries, screening of natural product sources yielded new small molecules that were subsequently identified as potent inhibitors of HDAC. While predominantly identified using antiproliferative assays, the biological activity of these new HDAC inhibitors also encompasses significant antiprotozoal, antifungal, phytotoxic and antiviral applications. These newly discovered HDAC inhibitors served as lead structures for the development of improved derivatives including related reagents with considerable potential as tools to further elucidate the mechanism of transcriptional regulation.

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Trichostatin C, a New Inducer of Differentiation of Friend Leukemic Cells

Cited by 6 publications

References 2 publications

Inhibition of Maize Histone Deacetylases by HC Toxin, the Host-Selective Toxin of Cochliobolus carbonum

Inhibition of Maize Histone Deacetylases by HC Toxin, the Host-Selective Toxin of Cochliobolus carbonum

Chemical and structural biology of protein lysine deacetylases

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

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