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Journal of Virology, April 2008, p. 3612-3623, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.02435-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cdc55p-Mediated E4orf4 Growth Inhibition in Saccharomyces cerevisiae Is Mediated Only in Part via the Catalytic Subunit of Protein Phosphatase 2A{triangledown}

Yikun Li,{dagger} Huijun Wei,{dagger},{ddagger} Tung-Chin Hsieh,§ and David C. Pallas*

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

Received 12 November 2007/ Accepted 16 January 2008

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 Saccharomyces cerevisiae, which provides a genetically tractable system for studying E4orf4 function. Interaction with the protein phosphatase 2A (PP2A) B regulatory subunit is required for E4orf4's effects, suggesting that E4orf4 may function by regulating B subunit-containing heterotrimeric PP2A holoenzymes (PP2ABAC), which consist of a 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 the PP2A C subunit or whether E4orf4 might have PP2A B subunit-dependent effects that are independent of PP2ABAC holoenzyme formation. To test these possibilities in S. cerevisiae, we disrupted the stable formation of PP2ABAC 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 PP2ABAC heterotrimers and through a B regulatory subunit-dependent pathway(s) that is independent of stable complex formation with the 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 anticancer therapies.

* Corresponding author. Mailing address: Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. Phone: (404) 727-5620. Fax: (404) 727-2738. E-mail: dpallas{at}emory.edu

{triangledown} Published ahead of print on 23 January 2008.

{dagger} Y.L. and H.W. contributed equally to this work.

{ddagger} Present address: Schering-Plough Research Institute, Kenilworth, NJ 07033.

§ Present address: Department of Urology, George Washington University, 2150 Pennsylvania Ave., NW, Washington, DC 20037.

Journal of Virology, April 2008, p. 3612-3623, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.02435-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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]  


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