Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells.

Ōmura, Satoshi; Fujimoto, Tomoko; Otoguro, Kazuhiko; Matsuzaki, Keiichi; Moriguchi, R; Tanaka, Haruo; Sasaki, Yasuharu

doi:10.7164/antibiotics.44.113

Cited by 510 publications

(244 citation statements)

References 13 publications

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“…Upon treatment of these resistant cells with lactacystin, a recently discovered Streptomyces metabolite (Omura et al, 1991) that specifically inhibits proteasome activity by a covalent alteration of the conserved amino-terminal threonine of the proteasome subunit X (Fontennay et al, 1995), cellular sensitivity to apoptosis induction by TNF-a was restored in a TNF-ax concentrationdependent manner ( Figure 2C). Moreover, the inhibition of the proteasomal-specific proteolytic activity by lactacystin alone was sufficient to render these malignant cells prone to apoptosis.…”

Section: Resultsmentioning

confidence: 97%

“…Lactacystin (Omura et al, 1991) was prepared as 3 mm stock solution in dry dimethyl sulphoxide (DMSO) and stored before use at -20°C. It was added directly to the cell culture immediately after irradiation at 1-10 gM final concentration and maintained in culture for 24 h. Any apoptotic effect was observed when DMSOonly cell treatment was used as control.…”

Section: Materials and Methods Isolation Of Human Lymphocytes And Detmentioning

confidence: 99%

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The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-α-initiated apoptosis

Delić¹,

Masdehors²,

Ōmura³

et al. 1998

Br J Cancer

183

112

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Summary Apoptosis can be triggered by cytotoxic agents and radiation currently used in cancer treatment. However, the apoptotic response appears to vary between cell types (normal or transformed) and between types of malignancy. Thus, irradiation induces apoptosis in normal human lymphocytes but not in lymphocytes derived from a subset of chronic lymphocytic leukaemia (CLL). Moreover, in this subset, spontaneous apoptosis is inhibited by irradiation. Why irradiation does not allow the initiation of the apoptotic death pathway could be explained, at least in part, and in agreement with recent findings on experimental models, by the activation of the transcriptional factor NF-KB, which is able to inhibit apoptotic cell response. Low doses (at which no effect is observed with normal human lymphocytes) of the highly specific proteasome inhibitor lactacystin are sufficient to trigger apoptosis in these malignant cells. Proteasome inhibition by lactacystin prevents the nuclear translocation of both p50 and p65 NF-KB subunits and sensitizes these cells to apoptosis by tumour necrosis factor (TNF)-a treatment. As this subset of CLL is totally resistant to any treatment, proteasome inhibition by lactacystin provides a new therapeutic approach to be explored, considering the sensitivity of malignant CLL-derived lymphocytes to be quite different from that of normal human lymphocytes.

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Section: Resultsmentioning

confidence: 97%

Section: Materials and Methods Isolation Of Human Lymphocytes And Detmentioning

confidence: 99%

The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-α-initiated apoptosis

Delić¹,

Masdehors²,

Ōmura³

et al. 1998

Br J Cancer

183

112

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“…For this investigation we chose lactacystin and epoxomicin as selective proteasome inhibitors because they both inhibit the chymotrypsin-like activity of the proteasome much faster than the trypsin-like and PGPH activities. Lactacystin is a Streptomyces metabolite that was discovered by virtue of its ability to induce cell cycle arrest and neurite outgrowth in a neuroblastoma line (21). The molecular target of lactacystin was later found to be the proteasome and, in particular, the N-terminal threonine residue of the ␤-type proteasome subunits MB-1 and, to a lesser extent, the subunit Z (5,22).…”

mentioning

confidence: 99%

The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses

Schwarz

Giuli

Schmidtke

et al. 2000

The Journal of Immunology

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The complete inhibition of proteasome activities interferes with the production of most MHC class I peptide ligands as well as with cellular proliferation and survival. In this study we have investigated how partial and selective inhibition of the chymotrypsin-like activity of the proteasome by the proteasome inhibitors lactacystin or epoxomicin would affect Ag presentation. At 0.5–1 μM lactacystin, the presentation of the lymphocytic choriomeningitis virus-derived epitopes NP118 and GP33 and the mouse CMV epitope pp89–168 were reduced and were further diminished in a dose-dependent manner with increasing concentrations. Presentation of the lymphocytic choriomeningitis virus-derived epitope GP276, in contrast, was markedly enhanced at low, but abrogated at higher, concentrations of either lactacystin or epoxomicin. The inhibitor-mediated effects were thus epitope specific and did not correlate with the degradation rates of the involved viral proteins. Although neither apoptosis induction nor interference with cellular proliferation was observed at 0.5–1 μM lactacystin in vivo, this concentration was sufficient to alter the fragmentation of polypeptides by the 20S proteasome in vitro. Our results indicate that partial and selective inhibition of proteasome activity in vivo is a valid approach to modulate Ag presentation, with potential applications for the treatment of autoimmune diseases and the prevention of transplant rejection.

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“…Antibody to ubiquitin was purchased from Sigma. Preparation of lactacystin has been described previously (10). All other chemical products were purchased from Sigma.…”

mentioning

confidence: 99%

Degradation of a Mutant Secretory Protein, α1-Antitrypsin Z, in the Endoplasmic Reticulum Requires Proteasome Activity

Teckman

Ōmura

et al. 1996

Journal of Biological Chemistry

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345

236

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Degradation of proteins that are retained in the quality control apparatus of the endoplasmic reticulum (ER) has been attributed to a third proteolytic system, distinct from the lysosomal and the cytoplasmic ubiquitindependent proteosomal proteolytic pathways. However, several recent studies have shown that ER degradation of a mutant membrane protein, CFTR⌬F508, is at least in part mediated from the cytoplasmic side by the 26 S proteasome. In this study, we examined the possibility that ER degradation of mutant secretory protein ␣ 1 -antitrypsin (␣ 1 -AT) Z, the mutant protein associated with infantile liver disease and adult-onset emphysema of ␣ 1 -AT deficiency, is mediated by the proteasome. The results show that a specific proteasome inhibitor, lactacystin, inhibits ER degradation of ␣1-ATZ in transfected human fibroblast cell lines and in a cell-free microsomal translocation system. Although it is relatively easy to conceptualize how a transmembrane protein like CFTR⌬F508 might be accessible on the cytoplasmic aspect of the ER membrane for ubiquitination and degradation by the proteasome, it is more difficult to conceptualize how this might occur for a luminal polypeptide. The results show that, once within the lumen of the ER, ␣ 1 -ATZ interacts with the transmembrane molecular chaperone calnexin and specifically induces the polyubiquitination of calnexin. The results, therefore, provide evidence that the proteasome, from its cytoplasmic localization, induces the degradation of the luminal ␣ 1 -ATZ molecule by first attacking the cytoplasmic tail of calnexin molecules that are associated with ␣ 1 -ATZ.

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Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells.

Cited by 510 publications

References 13 publications

The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-α-initiated apoptosis

The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-α-initiated apoptosis

The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses

Degradation of a Mutant Secretory Protein, α1-Antitrypsin Z, in the Endoplasmic Reticulum Requires Proteasome Activity

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