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

Recently, the oncoprotein MDM-2 was implicated in the transforming growth f actor-beta (TGF-beta) growth inhibitory pathway by the finding that prolong ed, constitutive expression of MDM-2 in mink lung epithelial cells could ov ercome the antiproliferative effect of TGF-beta (Sun, P., Dong, P., Dal, K. , Hannon, G. J., and Beach, D. (1998) Science 282, 2270-2272). However, usi ng Mv1Lu cells conditionally expressing MDM-2, we found that MDM-2 does not overcome TGF-beta-mediated growth arrest. No detectable changes were obser ved in various TGF-beta responses, including cell cycle arrest, activation of transcriptional reporters, and TGF-beta-dependent Smad2/3 nuclear accumu lation. 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, w hich renders cells refractory to TGF-beta-induced cell cycle arrest. Our re sults suggest that an MDM-2-dependent increase in cell cycle progression ma y allow the acquisition of additional mutations over time and that these al terations then allow cells to evade a TGF-beta-mediated growth arrest. Our conclusion is that, whereas c-Mye 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.