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Molecular and Cellular Biology, August 2003, p. 5446-5459, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5446-5459.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Defective T-Cell Activation Is Associated with Augmented Transforming Growth Factor ß Sensitivity in Mice with Mutations in the Sno Gene

S. Pearson-White1,2* and M. McDuffie1

Departments of Microbiology,1 Biochemistry and Molecular Genetics, University of Virginia Medical Center, Charlottesville, Virginia 229082

Received 31 January 2003/ Returned for modification 4 March 2003/ Accepted 8 May 2003

The proto-oncogene Sno has been shown to be a negative regulator of transforming growth factor beta (TGF-ß) signaling in vitro, using overexpression and artificial reporter systems. To examine Sno function in vivo, we made two targeted deletions at the Sno locus: a 5' deletion, with reduced Sno protein (hypomorph), and an exon 1 deletion removing half the protein coding sequence, in which Sno protein is undetectable in homozygotes (null). Homozygous Sno hypomorph and null mutant mice are viable without gross developmental defects. We found that Sno mRNA is constitutively expressed in normal thymocytes and splenic T cells, with increased expression 1 h following T-cell receptor ligation. Although thymocyte and splenic T-cell populations appeared normal in mutant mice, T-cell proliferation in response to activating stimuli was defective in both mutant strains. This defect could be reversed by incubation with either anti-TGF-ß antibodies or exogenous interleukin-2 (IL-2). Together, these findings suggest that Sno-dependent suppression of TGF-ß signaling is required for upregulation of growth factor production and normal T-cell proliferation following receptor ligation. Indeed, both IL-2 and IL-4 levels are reduced in response to anti-CD3{varepsilon} stimulation of mutant T cells, and transfected Sno activated an IL-2 reporter system in non-T cells. Mutant mouse embryo fibroblasts also exhibited a reduced cell proliferation rate that could be reversed by administration of anti-TGF-ß. Our data provide strong evidence that Sno is a significant negative regulator of antiproliferative TGF-ß signaling in both T cells and other cell types in vivo.

* Corresponding author. Mailing address: University of Virginia Health Sciences Center, Jordan Hall, Box 800734, Room 7034, Charlottesville, VA 22908-0734. Phone: (434) 982-0756. Fax: (434) 982-1071. E-mail: sp3i{at}virginia.edu.

Molecular and Cellular Biology, August 2003, p. 5446-5459, Vol. 23, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.15.5446-5459.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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