Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin

@article{Fenteany1995InhibitionOP,
  title={Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin},
  author={Gabriel Fenteany and Robert F Standaert and William Arbuthnot Sir Lane and S W Choi and E. J. Corey and Stuart L. Schreiber},
  journal={Science},
  year={1995},
  volume={268},
  pages={726 - 731}
}
Lactacystin is a Streptomyces metabolite that inhibits cell cycle progression and induces neurite outgrowth in a murine neuroblastoma cell line. Tritium-labeled lactacystin was used to identify the 20S proteasome as its specific cellular target. Three distinct peptidase activities of this enzyme complex (trypsin-like, chymotrypsin-like, and peptidylglutamyl-peptide hydrolyzing activities) were inhibited by lactacystin, the first two irreversibly and all at different rates. None of five other… Expand
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TLDR
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Catalytic activities of the 20 S proteasome, a multicatalytic proteinase complex.
TLDR
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References

SHOWING 1-10 OF 35 REFERENCES
A beta-lactone related to lactacystin induces neurite outgrowth in a neuroblastoma cell line and inhibits cell cycle progression in an osteosarcoma cell line.
TLDR
The observed structure-activity relationships suggest that lactacystin and its related beta-lactone may act via acylation of one or more relevant target molecule(s) in the cell to induce neurite outgrowth and inhibit progression of synchronized Neuro 2A cells and MG-63 human osteosarcoma cells beyond the G1 phase of the cell cycle. Expand
Relationships among the subunits of the high molecular weight proteinase, macropain (proteasome).
TLDR
Through a comparison of the 'latent' and 'active' forms of macropain, the study established a close similarity in the subunit composition of these catalytically very different species, although proteolytic degradation of selected subunits appears in the active form of the enzyme. Expand
Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules
TLDR
Peptide aldehydes that inhibit major peptidase activities of the 20S and 26S proteasomes are shown to reduce the degradation of protein and ubiquitinated protein substrates by 26S particles. Expand
Proteasome from Thermoplasma acidophilum: a threonine protease.
TLDR
The catalytic mechanism of the 20S proteasome from the archaebacterium Thermoplasma acidophilum has been analyzed by site-directed mutagenesis of the beta subunit and by inhibitor studies, and data show that the nucleophilic attack is mediated by the amino-terminal threonine of processed beta subunits. Expand
The ubiquitin-proteasome proteolytic pathway
TLDR
Two studies clearly demonstrate that the ubiquitin-proteasome system is involved not only in complete destruction of its protein substrates, but also in limited proteolysis and posttranslational processing in which biologically active peptides or fragments are generated. Expand
Homology of proteasome subunits to a major histocompatibility complex-linked LMP gene
TLDR
The isolation of a complementary DNA corresponding to one of the subunits of the LMP complex, LMP-2, closely matches the amino-terminal peptide sequence of a rat proteasome subunit, confirming that the proteasomesome and the L MP complex share polypeptide subunits. Expand
Proteasome components with reciprocal expression to that of the MHC-encoded LMP proteins
TLDR
It is suggested that the subtle phenotype of LMP-deficient cell lines results from the compensatory expression in these lines of two other proteasome subunits, MB1 and Delta. Expand
Nucleotide sequence of PUP1 encoding a putative proteasome subunit in Saccharomyces cerevisiae.
Proteasomes are ring-shaped 20 S particles that exhibit multiple proteolytic activities and are composed of several protein subunits and small RNAs (1 —4). They have been found in archaebacteria andExpand
Proteasomes: protein and gene structures.
TLDR
Evidence obtained by genetic analyses in yeast and studies on the levels of proteasome expression in various eukaryotic cells indicates that proteasomes have essential roles in the cell. Expand
PRE2, highly homologous to the human major histocompatibility complex-linked RING10 gene, codes for a yeast proteasome subunit necessary for chrymotryptic activity and degradation of ubiquitinated proteins.
TLDR
The cloned yeast PRE2 gene by complementation of pre2 mutants, which are defective in the chymotrypsin-like activity of the 20 S proteasome, suggests that replacement of constitutive proteasomal components by functionally related major histocompatibility complex-linked low molecular mass polypeptides, as is Ring10, adapts mammalian proteasomes for functions in the immune response. Expand
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