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Journal of Virology, February 2004, p. 1697-1705, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1697-1705.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Latent Membrane Protein 2A Inhibits Transforming Growth Factor-ß1-Induced Apoptosis through the Phosphatidylinositol 3-Kinase/Akt Pathway

Makoto Fukuda and Richard Longnecker*

Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Received 18 August 2003/ Accepted 27 October 2003

Latent membrane protein 2A (LMP2A) blocks B-cell receptor signal transduction in vitro by binding the Syk and Lyn protein tyrosine kinases. As well as blocking B-cell signal transduction, LMP2A has been shown to activate the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, which acts as a survival signal in both B cells and epithelial cells. Transforming growth factor ß1 (TGF-ß1) is a multifunctional cytokine that plays important roles in regulating cell growth and differentiation in many biological systems. The loss of the growth-inhibitory response to the TGF-ß1 signal is found in many cancers and is widely thought to promote tumor development. In this study, we found that LMP2A induced the phosphorylation of Akt (serine 473) in Burkitt's lymphoma cell line Ramos and in gastric carcinoma cell line HSC-39 and partially enhanced cell viability following TGF-ß1 treatment. In addition, LMP2A partially inhibited TGF-ß1-induced DNA fragmentation and cleavage of poly(ADP-ribose) polymerase (PARP). In the presence of LY294002, an inhibitor of PI3-K, the LMP2A-mediated inhibitory effects on TGF-ß1-induced DNA fragmentation and cleavage of PARP were alleviated. Furthermore, LMP2A did not alter the levels of expression of type I and type II TGF-ß1 receptors. Taken together, these results suggest that LMP2A may inhibit TGF-ß1-mediated apoptosis through activation of the PI3-K/Akt pathway.

* Corresponding author. Mailing address: Department of Microbiology-Immunology, Medical School, Northwestern University, 303 E. Chicago Ave., Chicago, IL 60611. Phone: (312) 503-0467. Fax: (312) 503-1339. E-mail: r-longnecker{at}northwestern.edu.

Journal of Virology, February 2004, p. 1697-1705, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1697-1705.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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