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A single Glu62-to-Lys62 mutation in the Mos residues of the R7Δ447Gag-tMos protein causes the mutant virus to induce brain lesions

Oncogene volume 20, pages 692–703 (2001)Cite this article

Abstract

We previously reported that R7Δ447, a 2954-base-pair (bp) laboratory-generated Moloney murine sarcoma virus, induced subcutaneous tumors in about 14% of infected mice but did not induce brain lesions. We now report that R7Δ447K, a spontaneous mutant of R7Δ447, induced brain lesions as well as subcutaneous tumors in all injected mice. The genomes of the two viruses differ in a single base pair: the deduced Glu62 of the Mos residue of the R7Δ447 Gag-tMos protein is changed to Lys62. More R7Δ447 than R7Δ447K focus-forming units were detected in both NIH3T3 and mouse cerebral vascular endothelial (MCVE) cells. However, R7Δ447K transformed NIH3T3 and MCVE cells more acutely than did R7Δ447. A distinctive feature that distinguished the morphologic transformation of R7Δ447- and R7Δ447K-infected MCVE cells is the markedly prolonged spindle-shaped phase exhibited by R7Δ447-infected MCVE cells. In addition, R7Δ447K was more efficient in inducing the phosphorylation of ERK1/2 than R7Δ447 in both MCVE and NIH3T3 cells. Moreover morphologic transformation was inhibited, and levels of phosphorylated ERK1/2 were reduced when R7Δ447- or R7Δ447K-infected NIH3T3 or MCVE cells were grown in the presence of the MEK1/2-specific inhibitor PD98095. Thus, we have identified a key residue in the Gag-tMos protein that profoundly affects activation of the Mos/MEK/ERK pathway, virus and cell replication, morphologic transformation in vitro and pathogenicity in vivo.

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Acknowledgements

We thank Sean Hensley and Dr Jianjun Shen of the Molecular Core at U.T.M.D. Anderson Cancer Center–Science Park for DNA sequencing and the Histology and Tissue Processing Core at U.T.M.D. Anderson Cancer Center–Science Park for histological processing. We also thank Judy Ing for assistance with the artwork, Dr Dennis Johnston for statistical analysis, and Kit Yeng Lim for technical assistance. We gratefully acknowledge the gift of MCVE cells isolated by Dr JR Welsh of Texas A&M University. Part of the sequencing and histological processing was supported by grant number ES07784 from the National Institute of Environmental Health Sciences.

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  1. Department of Carcinogenesis, Science Park–Research Division, The University of Texas M.D. Anderson Cancer Center, Smithville, TX 78957, Texas, USA

    P H Yuen, E A Ryan, E Devroe & P K Y Wong

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Yuen, P., Ryan, E., Devroe, E. et al. A single Glu62-to-Lys62 mutation in the Mos residues of the R7Δ447Gag-tMos protein causes the mutant virus to induce brain lesions. Oncogene 20, 692–703 (2001). https://doi.org/10.1038/sj.onc.1204150

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