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Journal of Virology, September 2003, p. 9324-9336, Vol. 77, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.17.9324-9336.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Transforming Growth Factor ß1 Receptor II Is Downregulated by E1A in Adenovirus-Infected Cells

Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63104

Received 21 February 2003/ Accepted 4 June 2003

Transforming growth factor ß1 (TGF-ß1) signaling is compromised in many tumors, thereby allowing the tumor to escape the growth-inhibitory and proapoptotic activities of the cytokine. Human adenoviruses interfere with a number of cellular pathways involved in cell cycle regulation and apoptosis, initially placing the cell in a "tumor-like" state by forcing quiescent cells into the cell cycle and also inhibiting apoptosis. We report that adenovirus-infected cells resemble tumor cells in that TGF-ß1 signaling is inhibited. The levels of TGF-ß1 receptor II (TßRII) in adenovirus-infected cells were decreased, and this decrease was mapped, by using virus mutants, to the E1A gene and to amino acids 2 to 36 and the C-terminal binding protein binding site in the E1A protein. The decrease in the TßRII protein was accompanied by a decrease in TßRII mRNA. The decrease in TßRII protein levels in adenovirus-infected cells was greater than the decrease in TßRII mRNA, suggesting that downregulation of the TßRII protein may occur through more than one mechanism. Surprisingly in this context, the half-lives of the TßRII protein in infected and uninfected cells were similar. TGF-ß1 signaling was compromised in cells infected with wild-type adenovirus, as measured with 3TP-lux, a TGF-ß-sensitive reporter plasmid expressing luciferase. Adenovirus mutants deficient in TßRII downregulation did not inhibit TGF-ß1 signaling. TGF-ß1 pretreatment reduced the relative abundance of adenovirus structural proteins in infected cells, an effect that was potentiated when cells were infected with mutants incapable of modulating the TGF-ß signaling pathway. These results raise the possibility that inhibition of TGF-ß signaling by E1A is a means by which adenovirus counters the antiviral defenses of the host.

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