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

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.