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J Virol, April 1998, p. 3221-3226, Vol. 72, No. 4
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Evidence of a Role for Phosphatidylinositol 3-Kinase Activation in the Blocking of Apoptosis by Polyomavirus Middle T Antigen

Jean Dahl,1 Annmarie Jurczak,1 Linda A. Cheng,1 David C. Baker,2 and Thomas L. Benjamin1,*

Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,1 and Department of Chemistry, The University of Tennessee, Knoxville, Tennessee 379962

Received 29 August 1997/Accepted 12 December 1997

A polyomavirus mutant (315YF) blocked in binding phosphatidylinositol 3-kinase (PI 3-kinase) has previously been shown to be partially deficient in transformation and to induce fewer tumors and with a significant delay compared to wild-type virus. The role of polyomavirus middle T antigen-activated PI 3-kinase in apoptosis was investigated as a possible cause of this behavior. When grown in medium containing 1D-3-deoxy-3-fluoro-myo-inositol to block formation of 3'-phosphorylated phosphatidylinositols, F111 rat fibroblasts transformed by wild-type polyomavirus (PyF), but not normal F111 cells, showed a marked loss of viability with evidence of apoptosis. Similarly, treatment with wortmannin, an inhibitor of PI 3-kinase, stimulated apoptosis in PyF cells but not in normal cells. Activation of Akt, a serine/threonine kinase whose activity has been correlated with regulation of apoptosis, was roughly twofold higher in F111 cells transformed by either wild-type virus or mutant 250YS blocked in binding Shc compared to cells transformed by mutant 315YF. In the same cells, levels of apoptosis were inversely correlated with Akt activity. Apoptosis induced by serum withdrawal in Rat-1 cells expressing a temperature-sensitive p53 was shown to be at least partially p53 independent. Expression of either wild-type or 250YS middle T antigen inhibited apoptosis in serum-starved Rat-1 cells at both permissive and restrictive temperatures for p53. Mutant 315YF middle T antigen was partially defective for inhibition of apoptosis in these cells. The results indicate that unlike other DNA tumor viruses which block apoptosis by inactivation of p53, polyomavirus achieves protection from apoptotic death through a middle T antigen-PI 3-kinase-Akt pathway that is at least partially p53 independent.

* Corresponding author. Mailing address: Department of Pathology, Harvard Medical School, 200 Longwood Ave., D2-230, Boston, MA 02115. Phone: (617) 432-1960. Fax: (617) 277-5291. E-mail: tbenjamin{at}warren.med.harvard.edu.




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