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Pivotal Advance: Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors.
MedLine Citation:
PMID:  22685320     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
A previously unsuspected, considerable proportion of newly synthesized polypeptides are hydrolyzed rapidly by proteasomes, possibly competing with endogenous substrates and altering proteostasis. In view of the anti-cancer effects of PIs, we set out to achieve a quantitative assessment of proteasome workload in cells hallmarked by different PI sensitivity, namely, a panel of MM cells, and in a dynamic model of plasma cell differentiation, a process that confers exquisite PI sensitivity. Our results suggest that protein synthesis is a key determinant of proteasomal proteolytic burden and PI sensitivity. In different MM cells and in differentiating plasma cells, the average proteolytic work accomplished per proteasome ranges over different orders of magnitude, an unexpected degree of variability, with increased workload invariably associated to increased PI sensitivity. The unfavorable load-versus-capacity balance found in highly PI-sensitive MM lines is accounted for by a decreased total number of immunoproteasomes/cell coupled to enhanced generation of RDPs. Moreover, indicative of cause-effect relationships, attenuating general protein synthesis by the otherwise toxic agent CHX reduces PI sensitivity in activated B and in MM cells. Our data support the view that in plasma cells protein synthesis contributes to determine PI sensitivity by saturating the proteasomal degradative capacity. Quantitating protein synthesis and proteasome workload may thus prove crucial to design novel negative proteostasis regulators against cancer.
Authors:
Simone Cenci; Laura Oliva; Fulvia Cerruti; Enrico Milan; Giada Bianchi; Mary Raule; Alexandre Mezghrani; Elena Pasqualetto; Roberto Sitia; Paolo Cascio
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-8
Journal Detail:
Title:  Journal of leukocyte biology     Volume:  -     ISSN:  1938-3673     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-6-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8405628     Medline TA:  J Leukoc Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
*Division of Genetics and Cell Biology, DiBiT, and.
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