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Journal of Virology, February 2001, p. 1816-1823, Vol. 75, No. 4
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.4.1816-1823.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Temperature-Sensitive Transformation by an Abelson Virus Mutant Encoding an Altered SH2 Domain

Celine A. Mainville,1,2 Kalindi Parmar,1,dagger Indira Unnikrishnan,1 Li Gong,3 Glen D. Raffel,3,4,Dagger and Naomi Rosenberg1,2,3,4,*

Departments of Pathology1 and Molecular Biology and Microbiology,3 Medical Scientist Training Program,4 and Graduate Program in Immunology,2 Tufts University School of Medicine, Boston, Massachusetts 02111

Received 17 August 2000/Accepted 20 November 2000

Abelson murine leukemia virus (Ab-MLV) encodes the v-Abl protein tyrosine kinase and induces transformation of immortalized fibroblast lines and pre-B cells. Temperature-sensitive mutations affecting the kinase domain of the protein have demonstrated that the kinase activity is absolutely required for transformation. Despite this requirement, mutations affecting other regions of v-Abl modulate transformation activity. The SH2 domain and the highly conserved FLVRES motif within it form a phosphotyrosine-binding pocket that is required for interactions between the kinase and cellular substrates. To understand the impact of SH2 alterations on Ab-MLV-mediated transformation, we studied the Ab-MLV mutant P120/R273K. This mutant encodes a v-Abl protein in which the beta B5 arginine at the base of the phosphotyrosine-binding pocket has been replaced by a lysine. Unexpectedly, infection of NIH 3T3 or pre-B cells with P120/R273K revealed a temperature-dependent transformation phenotype. At 34°C, P120/R273K transformed about 10-fold fewer cells than wild-type virus of equivalent titer; at 39.5°C, 300-fold fewer NIH 3T3 cells were transformed and pre-B cells were refractory to transformation. Temperature-dependent transformation was accompanied by decreased phosphorylation of Shc, a protein that interacts with the v-Abl SH2 and links the protein to Ras, and decreased induction of c-Myc expression. These data suggest that alteration of the FLVRES pocket affects the ability of v-Abl to interact with at least some of its substrates in a temperature-dependent fashion and identify a novel type of temperature-sensitive Abelson virus.

* Corresponding author. Mailing address: SC315, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. Phone: (617) 636-2143. Fax: (617) 636-0337. E-mail: nrosenbe{at}opal.tufts.edu.

dagger Present address: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA 02215.

Dagger Present address: Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215.

Journal of Virology, February 2001, p. 1816-1823, Vol. 75, No. 4
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.4.1816-1823.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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