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Molecular and Cellular Biology, March 2004, p. 2025-2040, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.2025-2040.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Defects in Translational Regulation Mediated by the {alpha} Subunit of Eukaryotic Initiation Factor 2 Inhibit Antiviral Activity and Facilitate the Malignant Transformation of Human Fibroblasts

Darren J. Perkins and Glen N. Barber*

Department of Microbiology and Immunology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136

Received 19 August 2003/ Returned for modification 25 September 2003/ Accepted 4 December 2003

Suppression of protein synthesis through phosphorylation of the translation initiation factor {alpha} subunit of eukaryotic initiation factor 2 (eIF2{alpha}) is known to occur in response to many forms of cellular stress. To further study this, we have developed novel cell lines that inducibly express FLAG-tagged versions of either the phosphomimetic eIF2{alpha} variant, eIF2{alpha}-S51D, or the phosphorylation-insensitive eIF2{alpha}-S51A. These variants showed authentic subcellular localization, were incorporated into endogenous ternary complexes, and were able to modulate overall rates of protein synthesis as well as influence cell division. However, phosphorylation of eIF2{alpha} failed to induce cell death or sensitize cells to killing by proapoptotic stimuli, though it was able to inhibit viral replication, confirming the role of eIF2{alpha} in host defense. Further, although the eIF2{alpha}-S51A variant has been shown to transform NIH 3T3 cells, it was unable to transform the murine fibroblast 3T3 L1 cell line. To therefore clarify this issue, we explored the role of eIF2{alpha} in growth control and demonstrated that the eIF2{alpha}-S51A variant is capable of collaborating with hTERT and the simian virus 40 large T antigen in the transformation of primary human kidney cells. Thus, dysregulation of translation initiation is indeed sufficient to cooperate with defined oncogenic elements and participate in the tumorigenesis of human tissue.

* Corresponding author. Mailing address: Room 511, Papanicolaou Bldg., 1550 NW 10th Ave. (M710), University of Miami School of Medicine, Miami, FL 33136. Phone: (305) 243-5914. Fax: (305) 243-5885. E-mail: gbarber{at}med.miami.edu.

Molecular and Cellular Biology, March 2004, p. 2025-2040, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.2025-2040.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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J. Bacteriol. J. Virol. Eukaryot. Cell
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Copyright © 2004 by the American Society for Microbiology. All rights reserved.