The ubiquitin‐proteasome pathway and proteasome inhibitors

Myung, Jayhyuk; Kim, Kyung Bo; Crews, Craig M.

doi:10.1002/med.1009

Cited by 395 publications

(266 citation statements)

References 263 publications

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“…The structural and functional information of proteasomes has allowed the design of small molecules to inhibit its proteolytic activity. These inhibitors, in most of the cases, block the chymotrypsin-like activity of β subunits either reversibly, such as MG132, or irreversibly such as lactacystin and epoxomicin (Kisselev and Goldberg, 2001;Myung et al, 2001).…”

Section: Figure 11: the Ubiquitin-proteasome System (Ups)mentioning

confidence: 99%

“…Hsp90 is a major cytosolic chaperone and has been shown to refold Fluc upon recovery from heat stress (Schneider et al, 1996). MG132 is a small molecule that reversibly inhibits the chymotrypsin-like activity of the proteasome and hence leads to accumulation of polyubiquitinated proteins in cells which causes proteome stress (Kisselev and Goldberg, 2001;Myung et al, 2001). We measured the effect of proteasome inhibition on Fluc-based sensors by fluorescence microscopy of HeLa cells that were (Figure 29c), which suggests that proteasome inhibition doesn't have a direct influence on the stability of Fluc-EGFP variants and therefore the aggregation of these sensor proteins could be caused by a general proteostasis imbalance.…”

Section: V34 Effect Of Fluc-egfp-based Sensors On the Cytosolic Stmentioning

confidence: 99%

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Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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Section: Figure 11: the Ubiquitin-proteasome System (Ups)mentioning

confidence: 99%

Section: V34 Effect Of Fluc-egfp-based Sensors On the Cytosolic Stmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…Defects in the complex biochemical machinery of UBP signalling pathway are linked to the pathogenesis of many human diseases (Myung et al, 2001). Targeting UBP signalling pathway has therapeutic implication.…”

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confidence: 99%

A novel proteasome inhibitor NPI-0052 as an anticancer therapy

2006

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Proteasome inhibitor Bortezomib/Velcade has emerged as an effective anticancer therapy for the treatment of relapsed and/or refractory multiple myeloma (MM), but prolonged treatment can be associated with toxicity and development of drug resistance. In this review, we discuss the recent discovery of a novel proteasome inhibitor, NPI-0052, that is distinct from Bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities; most importantly, it overcomes resistance to conventional and Bortezomib therapies. In vivo studies using human MM xenografts shows that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for Phase-I clinical trial of NPI-0052 in relapsed/ refractory MM patients. The systemic regulation of protein synthesis and protein degradation is essential for normal cellular functioning. The ubiquitinproteasome pathway mediates intracellular protein degradation: first, protein is marked with a chain of small polypeptides called ubiquitin; E1 ubiquitin enzyme then activates ubiquitin and links it to the ubiquitin-conjugating enzyme E2 in an ATP-dependent manner; E3 ubiquitin ligase then links the ubiquitin molecule to the protein; a long polypeptide chain of ubiquitin moieties is formed; and finally, a multi-enzyme proteolytic complex 26S proteasome degrades protein into small fragments in an ATPdependent manner.

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“…We have shown that the elimination of RPG1 is correlated with ubiquitination and the requirement of the chymotrypsinlike activity of the catalytic subunits in the 20S proteasome channel (40). Among the E3 ligases that bind the protein to be ubiquitinated, there is one family that recognizes substrates according to the end rule, preferring proteins with basic residues at the N terminus such as R, K, and H (40), often after removal of the N-terminal methionine.…”

Section: Discussionmentioning

confidence: 99%

Proteolysis of the barley receptor-like protein kinase RPG1 by a proteasome pathway is correlated with Rpg1 -mediated stem rust resistance

Nirmala¹,

Dahl

Steffenson

et al. 2007

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

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In plants, disease resistance mediated by the gene-for-gene mechanism involves the recognition of specific effector molecules produced by the pathogen either directly or indirectly by the resistance-gene products. This recognition triggers a series of signals, thereby serving as a molecular switch in regulating defense mechanisms by the plants. To understand the mechanism of action of the barley stem rust resistance gene Rpg1, we investigated the fate of the RPG1 protein in response to infection with the stem rust fungus, Puccinia graminis f. sp. tritici. The investigations revealed that RPG1 disappears to undetectable limits only in the infected tissues in response to avirulent, but not virulent pathotypes. The RPG1 protein disappearance is rapid and appears to be due to specific protein degradation via the proteasome-mediated pathway as indicated by inhibition with the proteasomal inhibitor MG132, but not by other protease inhibitors.avirulence ͉ cultivar ͉ programmed cell death ͉ Puccinia graminis P lants have evolved diverse mechanisms to recognize pathogen attack and trigger defense responses. Pathogen recognition specificity is often determined by a pathogen avirulence (Avr) gene and its corresponding plant resistance (R) gene in a gene for gene manner (1). The R gene products may function directly or indirectly as receptors for the Avr gene products, providing detection of pathogen attack (2-6). Avr proteins secreted from the pathogen are recognized by the R proteins either in the intercellular spaces or after their transport into the plant cell. The Avr-R interactions lead to activation of defense responses and often result in the hypersensitive response (HR) (1), inhibiting the growth of the pathogen. In the absence of either the cognate R or Avr gene product, the pathogen colonizes the host and causes disease. Despite the cloning of several R genes and their corresponding Avr genes, direct physical interaction between matched Avr and R proteins has been shown only in a few cases. To exemplify, the Avr-Pita protein of the rice blast fungus Magnaporthe grisea encoding a metalloprotease is secreted with an N-terminal signal sequence. After delivery into the plant cell and removal of the proprotein sequence, the mature enzyme binds to the leucine-rich domain of the Pi-ta R protein and elicits the resistance response. This interaction was confirmed with the yeast two-hybrid system, with transient expression in rice seedling leaves of resistant or susceptible lines, by in vitro binding of the recombinantly synthesized Pi-ta protein to the Avr-Pita protein and by inactivation of either of the proteins through amino acid substitutions (7). Direct physical interaction has been demonstrated for the tomato Pto R protein and the AvrPto gene product (2, 4), the Arabidopsis RRS1 R and Ralstonia solanacearum PopP2 (8), and between the flax R gene L6 with the corresponding Avr-L6 of Melampsora lini (9). However, attempts with other R-Avr pairs have failed to establish a direct physical interaction. These observations ...

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The ubiquitin‐proteasome pathway and proteasome inhibitors

Cited by 395 publications

References 263 publications

Firefly luciferase mutants as sensors of proteome stress

Firefly luciferase mutants as sensors of proteome stress

A novel proteasome inhibitor NPI-0052 as an anticancer therapy

Proteolysis of the barley receptor-like protein kinase RPG1 by a proteasome pathway is correlated with Rpg1 -mediated stem rust resistance

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