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Induction of Transforming Growth Factor β1 Resistance by the E1A Oncogene Requires Binding to a Specific Set of Cellular Proteins
Caterina Missero, Ellen Filvaroff and G. Paolo Dotto
Proceedings of the National Academy of Sciences of the United States of America
Vol. 88, No. 8 (Apr. 15, 1991), pp. 3489-3493
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/2356764
Page Count: 5
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Transforming growth factors β (TGF-β s) are potent inhibitors of epithelial cell growth in culture and might play a similar role in vivo. Several studies have suggested that acquisition of TGF-β resistance is an important step in epithelial tumor development. Here, we show that resistance to TGF-β1 growth inhibition can be induced by transformation of keratinocytes with the E1A, but not the ras, oncogene. Mutational analysis revealed that these effects closely correlate with the ability of E1A proteins to bind to the retinoblastoma gene product (p105) as well as to three other cellular proteins (p60, p107, and p300). Only partial resistance to TGF-β1 growth inhibition was elicited by E1A mutants that bind to a subset of proteins, whereas complete resistance was induced by E1A mutants that bind to all four proteins together. Total protection against TGF-β growth inhibition was also induced by concomitant introduction into cells of an E1A mutant binding to the p60/p105/p107 proteins and one binding to p300. In parallel with these effects, epidermal transglutaminase, a marker of keratinocyte differentiation, was induced by TGF-β in control but not in E1A-transformed cells. TGF-β1 receptor levels were only partially down-modulated by an intact E1A gene and not significantly affected by the various truncated mutants. Thus, the ability of E1A to induce TGF-β resistance depends on its ability to bind, and presumably inactivate, several cellular proteins that may be involved in transmission of the TGF-β signal and seem to act downstream from its receptor(s).
Proceedings of the National Academy of Sciences of the United States of America © 1991 National Academy of Sciences