Different sensitivity of the transforming growth factor-beta cell cycle arrest pathway to c-Myc and MDM-2 Journal Article
| Authors: | Blain, S. W.; Massagué, J. |
| Article Title: | Different sensitivity of the transforming growth factor-beta 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. |
| Keywords: | signal transduction; controlled study; unclassified drug; dna-binding proteins; proto-oncogene proteins; nonhuman; cell proliferation; animal cell; animals; cell cycle; cell division; cell growth; smad protein; smad2 protein; smad3 protein; transforming growth factor beta; transcription initiation; cell line; down-regulation; transfection; nuclear proteins; fluorescent antibody technique; myc protein; lung; genes, reporter; trans-activators; cell nucleus; proto-oncogene proteins c-myc; mutagenesis; protein mdm2; proto-oncogene proteins c-mdm2; mink; lung alveolus epithelium; trans-activation (genetics); priority journal; article |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 275 |
| Issue: | 41 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2000-10-13 |
| Start Page: | 32066 |
| End Page: | 32070 |
| Language: | English |
| PUBMED: | 10906337 |
| PROVIDER: | scopus |
| DOI: | 10.1074/jbc.M006496200 |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work