Estradiol stabilizes p53 protein in breast cancer cell line, MCF-7.
Overexpression of the oncoprotein MDM2, an important regulator of the p53 tumor suppressor protein, is often observed in breast cancer tissues and cell lines, particularly in those which express estrogen receptor alpha (ERalpha). In MCF-7 breast cancer cell line possessing wild-type p53, ERalpha, and overexpressing MDM2, p53 accumulation was stimulated by 17beta-estradiol (E2) in a concentration-dependent manner. On the other hand, E2 caused no change of the expression of p53 mRNA, indicating that E2 affects p53 at the post-transcriptional level. To analyze the mechanism of p53 accumulation by E2, the stability of p53, ERalpha and MDM2 proteins was analyzed in the presence of cycloheximide under an E2-supplemented or -depleted condition. E2 significantly extended the half-life of p53 protein, but shortened that of ERalpha in MCF-7 cells. E2 significantly decreased the stability of p90(MDM2) and p60(MDM2) in MCF-7. Interestingly, E2 increased the ratio p60(MDM2)/p90(MDM2) inversely proportionally to the degradation of p53. These results suggest that the ratio of the two MDM2 proteins, p90(MDM2) and p60(MDM2), may affect the accumulation of wild-type p53 protein in response to E2.
Okumura
Naoki
N
Second Department of Surgery, Gifu University School of Medicine, Gifu 500-8705, Japan. n-okumura@umin.ac.jp
Saji
Shigehira
S
Eguchi
Hidetaka
H
Hayashi
Shin-ichi
S
Saji
Shigetoyo
S
Nakashima
Shigeru
S
D015152:Blotting, Northern; D015153:Blotting, Western; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism
D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D012313:RNA; D003513:Cycloheximide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2