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.
Blain
S W
SW
Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Massagué
J
J
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter; D008168:Lung; D008907:Mink; D016296:Mutagenesis; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051736:Proto-Oncogene Proteins c-mdm2