JVI Accepts, published online ahead of print on 23 January 2008

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, Y. Articles by Pallas, D. C. Search for Related Content PubMed PubMed Citation Articles by Li, Y. Articles by Pallas, D. C.

 Previous Article  |  Next Article 

J. Virol. doi:10.1128/JVI.02435-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Cdc55p-mediated E4orf4 growth-inhibition in S. cerevisiae is mediated only in part via the catalytic subunit of PP2A

Yikun Li, Huijun Wei, Tung-Chin Hsieh, and David C. Pallas^*

Department of Biochemistry and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322

^* To whom correspondence should be addressed. Email: dpallas{at}emory.edu.

The adenovirus early region 4 open reading frame 4 (E4orf4) protein specifically induces p53-independent cell death of transformed but not normal human cells, suggesting that elucidation of its mechanism may provide important new avenues for cancer therapy. Wild-type E4orf4 and mutants that retain cancer cell toxicity also induce growth inhibition in S. cerevisiae, which provides a genetically tractable system for studying E4orf4 function. Interaction with PP2A B regulatory subunit is required for E4orf4's effects, suggesting that E4orf4 may function by regulating B subunit-containing heterotrimeric PP2A holoenzymes (PP2A_BAC), which consist of B subunit complexed with the PP2A structural (A) and catalytic (C) subunits. However, it is not known whether E4orf4-induced growth inhibition requires interaction with PP2A C subunit or whether E4orf4 might have PP2A B subunit-dependent effects that are independent of PP2A_BAC holoenzyme formation. To test these possibilities in S. cerevisiae, we disrupted the stable formation of PP2A_BAC heterotrimers and thus E4orf4/C subunit association by PP2A C subunit point mutations or by deletion of the gene for the PP2A methyltransferase, Ppm1p, and assayed for effects on E4orf4-induced growth inhibition. Our results support a model in which E4orf4 mediates growth inhibition and cell killing both through PP2A_BAC heterotrimers and through a B regulatory subunit-dependent pathway(s) that is independent of stable complex formation with PP2A C subunit. They also indicate that Ppm1p has a function other than regulating the assembly of PP2A heterotrimers and suggest that selective PP2A trimer inhibitors and PP6 inhibitors may be useful as adjuvant anti-cancer therapies.

This article has been cited by other articles:

• Li, S., Brignole, C., Marcellus, R., Thirlwell, S., Binda, O., McQuoid, M. J., Ashby, D., Chan, H., Zhang, Z., Miron, M.-J., Pallas, D. C., Branton, P. E. (2009). The Adenovirus E4orf4 Protein Induces G2/M Arrest and Cell Death by Blocking Protein Phosphatase 2A Activity Regulated by the B55 Subunit. J. Virol. 83: 8340-8352 [Abstract] [Full Text]  
• McCourt, P. C., Morgan, J. M., Nickels, J. T. Jr. (2009). Stress-induced Ceramide-activated Protein Phosphatase Can Compensate for Loss of Amphiphysin-like Activity In Saccharomyces cerevisiae and Functions to Reinitiate Endocytosis. J. Biol. Chem. 284: 11930-11941 [Abstract] [Full Text]