Lactacystin, a Specific Inhibitor of the Proteasome, Induces Apoptosis in Human Monoblast U937 Cells

Imajoh‐Ohmi, Shinobu; Kawaguchi, Takumi; Sugiyama, Sadao; Tanaka, Ken Ichiro; Ōmura, Satoshi; Kikuchi, Hidetomo

doi:10.1006/bbrc.1995.2878

Cited by 198 publications

(108 citation statements)

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“…Recently, several groups, including ours, found that proteasome inhibitors were potent apoptosis inducers when used in multiple cancer and transformed cell lines (10)(11)(12)(13). In addition, we also reported that inhibition of the proteasome activity was sufficient to overcome Bcl-2-or Bcr-Abl-mediated protective function from apoptosis (13,14).…”

mentioning

confidence: 77%

Bax degradation by the ubiquitin/proteasome-dependent pathway: Involvement in tumor survival and progression

Dou

2000

Proc. Natl. Acad. Sci. U.S.A.

410

311

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Previously we reported that proteasome inhibitors were able to overcome Bcl-2-mediated protection from apoptosis. Here we show that inhibition of the proteasome activity in Bcl-2-overexpressing cells accumulates the proapoptotic Bax protein to mitochondria͞cytoplasm, where it interacts to Bcl-2 protein. This event was followed by release of mitochondrial cytochrome c into the cytosol and activation of caspase-mediated apoptosis. In contrast, proteasome inhibition did not induce any apparent changes in Bcl-2 protein levels. In addition, treatment with a proteasome inhibitor increased levels of ubiquitinated forms of Bax protein, without any effects on Bax mRNA expression. We also established a cell-free Bax degradation assay in which an in vitro-translated, 35 S-labeled Bax protein can be degraded by a tumor cell protein extract, inhibitable by addition of a proteasome inhibitor or depletion of the proteasome or ATP. The Bax degradation activity can be reconstituted in the proteasome-depleted supernatant by addition of a purified 20S proteasome or proteasome-enriched fraction. Finally, by using tissue samples of human prostate adenocarcinoma, we demonstrated that increased levels of Bax degradation correlated well with decreased levels of Bax protein and increased Gleason scores of prostate cancer. Our studies strongly suggest that ubiquitin͞proteasome-mediated Bax degradation is a novel survival mechanism in human cancer cells and that selective targeting of this pathway should provide a unique approach for treatment of human cancers, especially those overexpressing Bcl-2.

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mentioning

confidence: 77%

Bax degradation by the ubiquitin/proteasome-dependent pathway: Involvement in tumor survival and progression

Dou

2000

Proc. Natl. Acad. Sci. U.S.A.

410

311

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“…Genetic evidence is consistent with an essential role for the ubiquitin (Ub)-proteasome system to maintain cell viability, and yeast whose proteasome activity is ablated are not viable (10,11). Exposure of mammalian cells to pharmacological agents that interfere with proteasome function generally leads to cell cycle arrest (12) and death (13). Proteasome inhibitors include the natural compounds lactacystin and epoxomycin (14,15) as well as C-terminally modified peptide derivatives (1,16), which all bind to the N-terminal threonine in the catalytic site of active ␤ subunits (17).…”

mentioning

confidence: 82%

Integration of the ubiquitin-proteasome pathway with a cytosolic oligopeptidase activity

Wang

Kessler

Borodovsky

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

108

118

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Cytosolic proteolysis is carried out predominantly by the proteasome. We show that a large oligopeptidase, tripeptidylpeptidase II (TPPII), can compensate for compromised proteasome activity. Overexpression of TPPII is sufficient to prevent accumulation of polyubiquitinated proteins and allows survival of EL-4 cells at otherwise lethal concentrations of the covalent proteasome inhibitor NLVS (NIP-leu-leu-leu-vinylsulfone). Elevated TPPII activity also partially restores peptide loading of MHC molecules. Purified proteasomes from adapted cells lack the chymotryptic-like activity, but still degrade longer peptide substrates via residual activity of their Z subunits. However, growth of adapted cells depends on induction of other proteolytic activities. Therefore, cytosolic oligopeptidases such as TPPII normalize rates of intracellular protein breakdown required for normal cellular function and viability.

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“…Human monoblast U937 cells grown in the presence of this agent had decreased viability, underwent morphologic changes suggestive of apoptosis, and their chromosomal DNA revealed fragmentation and laddering. 55 Subsequent investigators con®rmed the induction of apoptosis in U937 cells using peptidyl aldehyde proteasome inhibitors. 53 Studies evaluating the impact of a cell-permeable peptidyl aldehyde proteasome inhibitor on human T-cell leukemia MOLT-4 cells and mouse lymphocytic leukemia L5178Y cells showed that apoptosis was induced.…”

Section: The Proteasome and Apoptosis Correlation Of Apoptosis With Pmentioning

confidence: 99%

The role of the ubiquitin-proteasome pathway in apoptosis

1999

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Coordinated intracellular protein degradation mediated by the ubiquitin-proteasome pathway is crucial to a vast array of cellular processes including orderly progression through the mitotic cycle. Similarly important to both the fates of individual cells, as well as to the normal function of multicellular organisms, is the process of apoptosis, or programmed cell death. Execution of this latter process has been known for some time to be intimately associated with the activity of caspases, a family of proteases related to interleukin-1-b-converting enzyme. Evidence is now accumulating, however, that the ubiquitin-proteasome system itself plays an important role in apoptosis, and some of the cellular pathways that are impacted upon by the proteasome, and may lead to apoptosis, are beginning to be dissected. This review provides a summary of the experimental basis by which components of the ubiquitinproteasome pathway have been linked to apoptosis, and attempts are made to formulate a hypothesis about its role in this process.

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Lactacystin, a Specific Inhibitor of the Proteasome, Induces Apoptosis in Human Monoblast U937 Cells

Cited by 198 publications

References 0 publications

Bax degradation by the ubiquitin/proteasome-dependent pathway: Involvement in tumor survival and progression

Bax degradation by the ubiquitin/proteasome-dependent pathway: Involvement in tumor survival and progression

Integration of the ubiquitin-proteasome pathway with a cytosolic oligopeptidase activity

The role of the ubiquitin-proteasome pathway in apoptosis

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