Proteasome inhibitor induced gene expression profiles reveal overexpression of transcriptional regulators ATF3, GADD153 and MAD1

The ubiquitin/proteasome pathway has been implicated in a wide variety of c ellular processes and the number of substrates degraded by the proteasome i s impressive. Most prominently, the stability of a large number of transcri ption factors is regulated by ubiquitination. To elucidate pathways regulat ed by the proteasome, gene expression profiles were generated, comparing ch anges of mRNA expression of 7900 genes from the UniGene collection upon exp osure of cells to the proteasome inhibitors Lactacystin, Lactacystin-beta-l actone or MG132 by means of microarray based cDNA hybridization, The three profiles were very similar, but differed significantly from a gene expressi on profile generated with the histone deacetylase inhibitor Trapoxin A, ind icating that the observed alterations were indeed due to proteasome inhibit ion, Two of the most prominently induced genes encoded the growth arrest an d DNA damage inducible protein Gadd153 and the activating transcription fac tor ATF3, both transcription factors of the CCAAT/enhancer binding protein (C/EBP) family. ii third gene encoded for the transcriptional repressor and c-Myc antagonist Mad1. Our results suggest that proteasome inhibition lead s to upregulation of specific members of transcription factor families cont rolling cellular stress response and proliferation.