Subunit S5a of the 26S proteasome is regulated by antiapoptotic signals

Yael Gus, Rotem Karni, Alexander Levitzki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

We performed a functional genetic screen to find novel antiapoptotic genes that are under the regulation of the oncoprotein c-Src. Several clones were identified, including subunit S5a of the 26S proteasome. We found that S5a rescued Saos-2 cells from apoptosis induced by Src inhibitor 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1). S5a mRNA and protein levels were downregulated as a result of Src inhibition, either by siRNA or PP1. In cell lines that possess high activity of Src S5a levels were elevated. Cloning of the S5a promoter region showed that S5a transcription responds to several stimuli. Analysis of the promoter sequence revealed a binding site for Tcf/Lef-1 transcription factor. Indeed, β-catenin significantly induced transcription from the S5a promoter, whereas EMSA studies showed that Lef-1 binds the S5a promoter-binding site. Furthermore, we also found that PP1 and LY294002, but not PD98059 inhibit the S5a promoter activity. These results suggest that S5a is regulated during apoptosis at the transcriptional level and that S5a upregulation by antiapoptotic signals can contribute to cell survival.

Original languageAmerican English
Pages (from-to)2815-2831
Number of pages17
JournalFEBS Journal
Volume274
Issue number11
DOIs
StatePublished - Jun 2007

Keywords

  • Apoptosis
  • Beta-catenin
  • Proteasome
  • S5a
  • Src

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