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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 26Sproteasome. 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). | ỊFEBS Journal Subunit S5a of the 26S proteasome is regulated by antiapoptotic signals Yael Gus Rotem Karni and Alexander Levitzki The Hebrew University Department of BiologicalChemistry Silberman Institute Jerusalem Israel Keywords apoptosis beta-catenin proteasome S5a Src Correspondence A. Levitzki The Hebrew University Department of Biological Chemistry Silberman Institute Givat Ram Jerusalem 91904 Israel Fax 972 2 6512 958 Tel 972 2 6585 404 E-mail levitzki@vms.huji.ac.il Received 29 November 2006 revised 28 March 2007 accepted 30 March 2007 doi 10.1111 j.1742-4658.2007.05815.x 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 b-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 antia-poptotic signals can contribute to cell survival. Src family kinases are involved in numerous cellular processes such as cell differentiation proliferation cellcycle control receptor signaling and transformation 1-3 . The persistently activated unmutated form of c-Src as well as its abnormally high level of .
