Inhibition of proteasome activity induces concerted expression of proteasome genes and de novo formation of Mammalian proteasomes.
The 26 S proteasome is a high molecular mass proteinase complex that is built by at least 32 different protein subunits. Such protease complexes in bacteria and yeast are systems that undergo a highly sophisticated network of gene expression regulation. However, regulation of mammalian proteasome gene expression has been neglected so far as a possible control mechanism for the amount of proteasomes in the cell. Here, we show that treatment of cells with proteasome inhibitors and the concomitant impairment of proteasomal enzyme activity induce a transient and concerted up-regulation of all mammalian 26 S proteasome subunit mRNAs. Proteasome inhibition in combination with inhibition of transcription revealed that the observed up-regulation is mediated by coordinated transcriptional activation of the proteasome genes and not by post-transcriptional events. Our experiments also demonstrate that inhibitor-induced proteasome gene activation results in enhanced de novo protein synthesis of all subunits and in increased de novo formation of proteasomes. This phenomenon is accompanied by enhanced expression of the proteasome maturation factor POMP. Thus, our experiments present the first evidence that the amount of proteasomes in mammalia is regulated at the transcriptional level and that there exists an autoregulatory feedback mechanism that allows the compensation of reduced proteasome activity.
Meiners
Silke
S
Humboldt Universität zu Berlin, Universitätsklinikum Charité, Institut für Biochemie, Monbijoustrasse 2, 10117 Berlin, Germany.
Heyken
Dirk
D
Weller
Andrea
A
Ludwig
Antje
A
Stangl
Karl
K
Kloetzel
Peter-M
PM
Krüger
Elke
E
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002499:Centrifugation, Density Gradient; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D018832:Molecular Chaperones / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013395:Sucrose / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018832:Molecular Chaperones; D011480:Protease Inhibitors; C110856:proteasome maturation protein; D013395:Sucrose; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease