Analysis of molecular mechanism in endometrial cancer development.

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We previously reported that enhanced transcriptional activation of estrogen receptorα(ERα) contributed to [^<12> Val] K-Ras mediated NIH3T3 cell transformation. Functional inactivation of ERα by a dominant negative mutant of ERα (DNER) in the presence of activated K-Ras 4B mutant arrested the cell cycle at G0/G1, subsequently provoking replicative cell senescence, finally abrogating tumorigenic potential. p53-dependent up-regulation 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 4B 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 ERα 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 ERα-APl pathway activated by oncogenic K-Ras 4B mutant contributes to the NIH3T3 cells' transformation by modulating p53 transcriptional activity through MDM2.