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Originally published In Press as doi:10.1074/jbc.M006496200 on July 21, 2000

J. Biol. Chem., Vol. 275, Issue 41, 32066-32070, October 13, 2000
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Different Sensitivity of the Transforming Growth Factor-beta Cell Cycle Arrest Pathway to c-Myc and MDM-2*

Stacy W. BlainDagger and Joan Massagué§

From the Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Recently, the oncoprotein MDM-2 was implicated in the transforming growth factor-beta (TGF-beta ) growth inhibitory pathway by the finding that prolonged, constitutive expression of MDM-2 in mink lung epithelial cells could overcome the antiproliferative effect of TGF-beta (Sun, P., Dong, P., Dai, K., Hannon, G. J., and Beach, D. (1998) Science 282, 2270-2272). However, using Mv1Lu cells conditionally expressing MDM-2, we found that MDM-2 does not overcome TGF-beta -mediated growth arrest. No detectable changes were observed in various TGF-beta responses, including cell cycle arrest, activation of transcriptional reporters, and TGF-beta -dependent Smad2/3 nuclear accumulation. This finding was in direct contrast to the effect of forcing c-Myc expression, a bona fide member of the TGF-beta growth inhibitory pathway, which renders cells refractory to TGF-beta -induced cell cycle arrest. Our results suggest that an MDM-2-dependent increase in cell cycle progression may allow the acquisition of additional mutations over time and that these alterations then allow cells to evade a TGF-beta -mediated growth arrest. Our conclusion is that, whereas c-Myc down-regulation by TGF-beta is a required event in the cell cycle arrest response of epithelial cells, MDM-2 is not a direct participant in the normal TGF-beta antiproliferative response.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Special Fellow of the Leukemia and Lymphoma Society.

§ Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Memorial Sloan-Kettering Cancer Center, P. O. Box 116, 1275 York Ave., New York, NY 10021. Tel.: 212-639-8975; Fax: 212-717-3298; E-mail: j-massague@ski.mskcc.org.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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