Different sensitivity of the transforming growth factor-ß cell cycle arrest pathway to c-Myc and IMDM-2
Different sensitivity of the transforming growth factor-ß cell cycle arrest pathway to c-Myc and IMDM-2
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DOI：
10.1074/jbc.m006496200
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发表时间：
2000-10-13
影响因子：
4.8
通讯作者：
Massagué, J
中科院分区：
文献类型：
--
作者：
Blain, SW;Massagué, J
最近，肿瘤蛋白MDM-2与转化生长因子- β (tgf - β)生长抑制途径有关，发现MDM-2在水貂肺上皮细胞中长期的组成性表达可以克服tgf - β的抗增殖作用（Sun， P., Dong， P., Dal， K., Hannon， G. J., and Beach， D. (1998) Science 282, 2270-2272）。然而，使用条件表达MDM-2的Mv1Lu细胞，我们发现MDM-2不能克服tgf - β介导的生长停滞。在各种tgf - β反应中未观察到可检测到的变化，包括细胞周期阻滞、转录报告基因的激活和tgf - β依赖的Smad2/3核积累。这一发现与强迫c-Myc表达的效果直接相反，c-Myc是tgf - β生长抑制途径的真正成员，它使细胞难以抵抗tgf - β诱导的细胞周期停滞。我们的研究结果表明，细胞周期进程中mdm -2依赖性的增加可能允许随着时间的推移获得额外的突变，这些改变随后允许细胞逃避tgf - β介导的生长停滞。我们的结论是，尽管tgf - β对c-Mye的下调是上皮细胞细胞周期阻滞反应的必要事件，但MDM-2并不是正常tgf - β抗增殖反应的直接参与者。
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., Dal, 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-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.