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

Oncogene volume 19, pages 2913–2920 (2000)Cite this article

Abstract

The ubiquitin/proteasome pathway has been implicated in a wide variety of cellular processes and the number of substrates degraded by the proteasome is impressive. Most prominently, the stability of a large number of transcription factors is regulated by ubiquitination. To elucidate pathways regulated by the proteasome, gene expression profiles were generated, comparing changes of mRNA expression of 7900 genes from the UniGene collection upon exposure of cells to the proteasome inhibitors Lactacystin, Lactacystin-β-lactone or MG132 by means of microarray based cDNA hybridization. The three profiles were very similar, but differed significantly from a gene expression profile generated with the histone deacetylase inhibitor Trapoxin A, indicating that the observed alterations were indeed due to proteasome inhibition. Two of the most prominently induced genes encoded the growth arrest and DNA damage inducible protein Gadd153 and the activating transcription factor ATF3, both transcription factors of the CCAAT/enhancer binding protein (C/EBP) family. A third gene encoded for the transcriptional repressor and c-Myc antagonist Mad1. Our results suggest that proteasome inhibition leads to upregulation of specific members of transcription factor families controlling cellular stress response and proliferation.

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Acknowledgements

We are grateful to the staff at Incyte Inc. (Palo Alto, CA, USA) for performing the array based hybridizations. We thank Lidia Sambucetti for Trapoxin A and Johannes Roesel for his constructive comments on the manuscript.

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Authors and Affiliations

  1. Novartis Pharma AG, Oncology Research, WKL-125.13.14, Basel, CH-4002, Switzerland

    Johann Zimmermann, Dirk Erdmann, Isabelle Lalande, Rita Grossenbacher, Maria Noorani & Peter Fürst

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  1. Johann Zimmermann
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  2. Dirk Erdmann
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Zimmermann, J., Erdmann, D., Lalande, I. et al. Proteasome inhibitor induced gene expression profiles reveal overexpression of transcriptional regulators ATF3, GADD153 and MAD1. Oncogene 19, 2913–2920 (2000). https://doi.org/10.1038/sj.onc.1203606

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