Different sensitivity of the transforming growth factor-β cell cycle arrest pathway to c-Myc and MDM-2

Abstract

Recently, the oncoprotein MDM-2 was implicated in the transforming growth factor-β (TGF-β) growth inhibitory pathway by the finding that prolonged, constitutive exression of MDM-2 in mink lung epithelial cells could overcome the antiproliferative effect of TGF-β (Sun, P., Dong, P., Dai, K., Harmon, 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-β-mediated growth arrest. No detectable changes were observed in various TGF-β responses, including cell cycle arrest, activation of transcriptional reporters, and TGF-β-dependent Smad2/3 nuclear accumulation. This finding was in direct contrast to the effect of forcing c-Myc exression, a bona fide member of the TGF-β growth inhibitory pathway, which renders cells refractory to TGF-β-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-β-mediated growth arrest. Our conclusion is that, whereas c-Myc down-regulation by TGF-β is a required event in the cell cycle arrest response of epithelial cells, MDM-2 is not a direct participant in the nodal TGF-β antiproliferative response.