Proteasomes are essential for yeast proliferation. cDNA cloning and gene disruption of two major subunits.

Fujiwara, Tsutomu; Tanaka, Keiji; Orino, Etsuko; Yoshimura, Teizo; Kumatori, Atsushi; Tamura, Tomohiro; Chung, Chin Ha; Nakai, Toshiki; Yamaguchi, Kyoko; Shin, Sadahito

doi:10.1016/s0021-9258(17)46265-x

Cited by 126 publications

(17 citation statements)

References 49 publications

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“…Here, we developed similar assays using available yeast strains in which the essential CP subunit Pre10 (a 7 ) and the RP subunit Rpn5 were genetically replaced with versions bearing a C-terminal GFP. Rescue of the lethal phenotype of Dpre10 and Drpn5 cells by these GFP fusions confirmed their functionality (Figure 1A) (Fujiwara et al, 1990;Saito et al, 1997).…”

Section: Resultssupporting

confidence: 52%

Autophagic Turnover of Inactive 26S Proteasomes in Yeast Is Directed by the Ubiquitin Receptor Cue5 and the Hsp42 Chaperone

2016

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The autophagic clearance of 26S proteasomes (proteaphagy) is an important homeostatic mechanism within the ubiquitin system that modulates proteolytic capacity and eliminates damaged particles. Here, we define two proteaphagy routes in yeast that respond to either nitrogen starvation or particle inactivation. Whereas the core autophagic machineries required for Atg8 lipidation and vesiculation are essential for both routes, the upstream Atg1 kinase participates only in starvation-induced proteaphagy. Following inactivation, 26S proteasomes become extensively modified with ubiquitin. Although prior studies with Arabidopsis implicated RPN10 in tethering ubiquitylated proteasomes to ATG8 lining the autophagic membranes, yeast proteaphagy employs the evolutionarily distinct receptor Cue5, which simultaneously binds ubiquitin and Atg8. Proteaphagy of inactivated proteasomes also requires the oligomeric Hsp42 chaperone, suggesting that ubiquitylated proteasomes are directed by Hsp42 to insoluble protein deposit (IPOD)-type structures before encapsulation. Together, Cue5 and Hsp42 provide a quality control checkpoint in yeast directed at recycling dysfunctional 26S proteasomes.

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Section: Resultssupporting

confidence: 52%

Autophagic Turnover of Inactive 26S Proteasomes in Yeast Is Directed by the Ubiquitin Receptor Cue5 and the Hsp42 Chaperone

2016

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“…When bortezomib-resistant patient samples were analyzed, however, no PSMB5 mutations were identified [107][108][109] . This finding is consistent with early studies showing that mutations in genes encoding proteasome subunits tend to result in a lethal phenotype in yeast 110 . The overexpression of proteasome subunit β5 and other subunits, such as β2 and β1, has also been detected in cell lines derived from Burkitt lymphoma, myeloid leukaemia, plasmacytoid lymphoma, and myeloma, and has been reported to act as possible mechanisms of resistance to bortezomib [111][112][113] .…”

Section: Resistance To Proteasome Inhibitorssupporting

confidence: 93%

Proteasome Inhibitors in Cancer Therapy

Orłowski

Ubiquitin-Proteasome Protocols

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Inhibitors of the proteasome have long been used in studies of protein turnover, but in a notable example of successful translational research they have made the leap from the laboratory into the clinical arena. The proteasome inhibitor bortezomib (VELCADE, formerly known as PS-341), has recently been approved in the United States for treatment of patients with multiple myeloma who have received at least two prior therapies, and have demonstrated disease progression on their last therapy. Furthermore, studies of this agent in other hematologic malignancies and solid tumors are underway, and other proteasome inhibitors for clinical use are under development as well. This chapter provides the reader with guidelines for the optimal clinical administration of VELCADE for its currently approved indication, as well as some suggestions for subsequent management of treatment-related events in these patients.

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“…Proteasome is a unique high-molecular-mass protease complex of 22-31 kDa subunits, and possesses several distinct catalytic activities. Since gene disruption of proteasome subunits is lethal for yeast, proteasome is essential for cell proliferation [17]. In mammalian cells, proteasome is abundantly expressed in malignant leukaemia cells.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis induction resulting from proteasome inhibition

Shinohara

Tomioka

Nakano

et al. 1996

Biochemical Journal

225

135

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Proteases are known to be involved in the apoptotic pathway. We report here that benzyloxycarbonyl (Z)-Leu-Leu-leucinal(ZLLLal), a leupeptin analogue, can induce apoptosis in MOLT-4 and L5178Y cells. ZLLLal is a cell-permeant inhibitor of proteasome. Among the protease inhibitors tested, only calpain inhibitor I (acetyl-Leu-Leu-norleucinal) and ZLLLal caused a marked induction of apoptosis in MOLT-4 cells. In contrast Z-Leu-leucinal, a specific inhibitor of calpain, did not induce apoptosis. When MOLT-4 cells were incubated in the presence of ZLLLal, p53 accumulated in the cells. These results strongly suggest that inhibition of proteasome induces p53-dependent apoptosis and that proteasome can protect cell from apoptosis.

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Proteasomes are essential for yeast proliferation. cDNA cloning and gene disruption of two major subunits.

Cited by 126 publications

References 49 publications

Autophagic Turnover of Inactive 26S Proteasomes in Yeast Is Directed by the Ubiquitin Receptor Cue5 and the Hsp42 Chaperone

Autophagic Turnover of Inactive 26S Proteasomes in Yeast Is Directed by the Ubiquitin Receptor Cue5 and the Hsp42 Chaperone

Proteasome Inhibitors in Cancer Therapy

Apoptosis induction resulting from proteasome inhibition

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