Implication of proteasome in estrogen receptor degradation.
In MCF-7 breast cancer cells, estradiol (E2) and pure antiestrogen RU 58668 down-regulate the estrogen receptor (ER). Interestingly, the protein synthesis inhibitor cycloheximide (CHX) abrogated solely the effect of E2 suggesting a selective difference in the degradation of the receptor induced by estrogenic and antiestrogenic stimulations. A panel of lysosome inhibitors (i.e. bafilomycin, chloroquine, NH4Cl, and monensin), calpain inhibitors (calpastatin and PD 150606) and proteasome inhibitors (lactacystin and proteasome inhibitor I) were tested to assess this hypothesis. Among all inhibitors tested, lactacystin and proteasome inhibitor I were the sole inhibitors to abrogate the elimination of the receptor induced by both E2 and RU 58668; this selective effect was also recorded in cells prelabeled with [3H]tamoxifen aziridine before exposure to these ligands. Hence, differential sensitivity to CHX seems to be linked to the different mechanisms which target proteins for proteasome-mediated destruction. Moreover, the two tested proteasome inhibitors produced a slight increase of ER concentration in cells not exposed to any ligand, suggesting also the involvement of proteasome in receptor turnover.
El Khissiin
A
A
Laboratoire J.C. Heuson de Cancérologie Mammaire, Service de Médecine, Institut Jules Bordet, Brussels, Belgium.
Leclercq
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G
D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism*; D014316:Tritium; D014407:Tumor Cells, Cultured
D015853:Cysteine Proteinase Inhibitors; D008024:Ligands; D009097:Multienzyme Complexes; D011500:Protein Synthesis Inhibitors; D011960:Receptors, Estrogen; D014316:Tritium; D004958:Estradiol; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex