Differential regulation of estrogen receptor alpha turnover and transactivation by Mdm2 and stress-inducing agents.
In mammalian cells, the level of estrogen receptor alpha (ERalpha) is rapidly decreased upon estrogen treatment, and this regulation involves proteasome degradation. Using different approaches, we showed that the Mdm2 oncogenic ubiquitin-ligase directly interacts with ERalpha in a ternary complex with p53 and is involved in the regulation of ERalpha turnover (both in the absence or presence of estrogens). Several lines of evidence indicated that this effect of Mdm2 required its ubiquitin-ligase activity and involved the ubiquitin/proteasome pathway. Moreover, in MCF-7 human breast cancer cells, various p53-inducing agents (such as UV irradiation) or treatment with RITA (which inhibits the interaction of p53 with Mdm2) stabilized ERalpha and abolished its 17beta-estradiol-dependent turnover. Interestingly, our data indicated that ligand-dependent receptor turnover was not required for efficient transactivation. Altogether, our results indicate that the Mdm2 oncoprotein and stress-inducing agents complexly and differentially regulate ERalpha stability and transcriptional activity in human cancer cells.
Duong
Vanessa
V
Institut National de la Santé et de la Recherche Médicale U540, Montpellier, France.
Boulle
Nathalie
N
Daujat
Sylvain
S
Chauvet
Jérôme
J
Bonnet
Sandrine
S
Neel
Henry
H
Cavaillès
Vincent
V
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D007976:Leupeptins / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D007976:Leupeptins; D009363:Neoplasm Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C403666:ZNF331 protein, human; D004958:Estradiol; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde