Contribution of estrogen receptor α to oncogenic K-Ras-mediated NIH3T3 cell transformation and its implication for escape from senescence by modulating the p53 pathway
Contribution of estrogen receptor α to oncogenic K-Ras-mediated NIH3T3 cell transformation and its implication for escape from senescence by modulating the p53 pathway
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DOI：
10.1074/jbc.m107391200
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发表时间：
2002-03-29
影响因子：
4.8
通讯作者：
Wake, N
中科院分区：
文献类型：
--
作者：
Kato, K;Horiuchi, S;Wake, N
我们先前报道了增强的雌激素受体α（ER α）转录激活有助于[（12）瓦尔]K-Ras介导的NIH 3 T3细胞转化。在激活的K-Ras 4 B突变体存在下，ER α显性失活突变体（DNER）使ER α功能失活，将细胞周期阻滞在G（0）/G（1），随后引起复制性细胞衰老，最终消除致瘤潜力。p21的p53依赖性上调与该细胞衰老诱导有关。响应DNER的MDM 2蛋白的改变解释了这种p21介导的细胞衰老诱导。致癌性K-Ras 413突变体显著增加与p53共沉淀的MDM 2蛋白，并抑制p53转录活性。反过来，DNER发挥其功能，减少MDM 2蛋白与p53共沉淀，随后刺激p53活性的致癌K-Ras 4 B突变体的存在。此外，野生型ER α在NIH 3 T3细胞中的过表达导致MDM 2蛋白水平的显著增加和p53转录活性的抑制。最后，我们证明了c-Jun表达克服了DNER对p21蛋白水平的抑制和由此产生的增强。这些数据表明，致癌K-Ras 413突变体激活的ER α-AP 1通路通过MDM 2调节p53转录活性而有助于NIH 3 T3细胞的转化。
We previously reported that enhanced transcriptional activation of estrogen receptor alpha (ERalpha) contributed to [(12)Val]K-Ras-mediated NIH3T3 cell transformation. Functional inactivation of ERalpha by a dominant negative mutant of ERalpha (DNER) in the presence of activated K-Ras 4B mutant arrested the cell cycle at G(0)/G(1), subsequently provoking replicative cell senescence, finally abrogating tumorigenic potential. p53-dependent upregulation of p21 was implicated in this cell senescence induction. Alterations in the MDM2 protein in response to DNER accounted for this p21-mediated cell senescence induction. An oncogenic K-Ras 413 mutant significantly increased MDM2 proteins coprecipitated with p53, and suppressed p53 transcriptional activity. In turn, DNER exerted its function to decrease MDM2 proteins coprecipitated with p53, followed by the stimulation of p53 activity in the presence of the oncogenic K-Ras 4B mutant. In addition, overexpression of wild type ERalpha in NIH3T3 cells resulted in the significant increase in the MDM2 protein level and the resultant suppression of p53 transcriptional activity. Finally, we demonstrated that c-Jun expression overcame the suppression and resultant enhancement of p21 protein level in response to DNER. The data imply that the ERalpha-AP1 pathway activated by oncogenic K-Ras 413 mutant contributes to the NIH3T3 cells' transformation by modulating p53 transcriptional activity through MDM2.