The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor
Fulvestrant, a selective estrogen receptor down-regulator (SERD) is a pure competitive antagonist of estrogen receptor alpha (ERα). Fulvestrant binds ERα and reduces the receptor's half-life by increasing protein turnover, however, its mechanism of action is not fully understood. In this study,...
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todo:paper_03037207_v415_n_p76_Casa2023-10-03T15:19:57Z The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor Casa, A.J. Hochbaum, D. Sreekumar, S. Oesterreich, S. Lee, A.V. Breast cancer Degradation Endocrine therapy Estrogen receptor Fulvestrant Nuclear localization sequence estradiol estrogen receptor alpha fulvestrant estradiol estrogen receptor alpha fulvestrant amino acid sequence amino terminal sequence antineoplastic activity Article controlled study drug receptor binding gene mutation human human cell ligand binding molecular cloning priority journal protein degradation protein domain protein function protein localization protein processing protein targeting sequence analysis sumoylation analogs and derivatives cell nucleus drug effects genetics HEK293 cell line MCF 7 cell line metabolism mutation protein degradation Cell Nucleus Estradiol Estrogen Receptor alpha HEK293 Cells Humans MCF-7 Cells Mutation Proteolysis Sumoylation Fulvestrant, a selective estrogen receptor down-regulator (SERD) is a pure competitive antagonist of estrogen receptor alpha (ERα). Fulvestrant binds ERα and reduces the receptor's half-life by increasing protein turnover, however, its mechanism of action is not fully understood. In this study, we show that removal of the ERα nuclear localization sequence (ERδNLS) resulted in a predominantly cytoplasmic ERα that was degraded in response to 17-β-estradiol (E2) but was resistant to degradation by fulvestrant. ERδNLS bound the ligands and exhibited receptor interaction similar to ERα, indicating that the lack of degradation was not due to disruption of these processes. Forcing ERδNLS into the nucleus with a heterologous SV40-NLS did not restore degradation, suggesting that the NLS domain itself, and not merely receptor localization, is critical for fulvestrant-induced ERα degradation. Indeed, cloning of the endogenous ERα NLS onto the N-terminus of ERδNLS significantly restored both its nuclear localization and turnover in response to fulvestrant. Moreover, mutation of the sumoylation targets K266 and K268 within the NLS impaired fulvestrant-induced ERα degradation. In conclusion, our study provides evidence for the unique role of the ERα NLS in fulvestrant-induced degradation of the receptor. © 2015 Elsevier Ireland Ltd. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_03037207_v415_n_p76_Casa |
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Universidad de Buenos Aires |
| institution_str |
I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Breast cancer Degradation Endocrine therapy Estrogen receptor Fulvestrant Nuclear localization sequence estradiol estrogen receptor alpha fulvestrant estradiol estrogen receptor alpha fulvestrant amino acid sequence amino terminal sequence antineoplastic activity Article controlled study drug receptor binding gene mutation human human cell ligand binding molecular cloning priority journal protein degradation protein domain protein function protein localization protein processing protein targeting sequence analysis sumoylation analogs and derivatives cell nucleus drug effects genetics HEK293 cell line MCF 7 cell line metabolism mutation protein degradation Cell Nucleus Estradiol Estrogen Receptor alpha HEK293 Cells Humans MCF-7 Cells Mutation Proteolysis Sumoylation |
| spellingShingle |
Breast cancer Degradation Endocrine therapy Estrogen receptor Fulvestrant Nuclear localization sequence estradiol estrogen receptor alpha fulvestrant estradiol estrogen receptor alpha fulvestrant amino acid sequence amino terminal sequence antineoplastic activity Article controlled study drug receptor binding gene mutation human human cell ligand binding molecular cloning priority journal protein degradation protein domain protein function protein localization protein processing protein targeting sequence analysis sumoylation analogs and derivatives cell nucleus drug effects genetics HEK293 cell line MCF 7 cell line metabolism mutation protein degradation Cell Nucleus Estradiol Estrogen Receptor alpha HEK293 Cells Humans MCF-7 Cells Mutation Proteolysis Sumoylation Casa, A.J. Hochbaum, D. Sreekumar, S. Oesterreich, S. Lee, A.V. The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor |
| topic_facet |
Breast cancer Degradation Endocrine therapy Estrogen receptor Fulvestrant Nuclear localization sequence estradiol estrogen receptor alpha fulvestrant estradiol estrogen receptor alpha fulvestrant amino acid sequence amino terminal sequence antineoplastic activity Article controlled study drug receptor binding gene mutation human human cell ligand binding molecular cloning priority journal protein degradation protein domain protein function protein localization protein processing protein targeting sequence analysis sumoylation analogs and derivatives cell nucleus drug effects genetics HEK293 cell line MCF 7 cell line metabolism mutation protein degradation Cell Nucleus Estradiol Estrogen Receptor alpha HEK293 Cells Humans MCF-7 Cells Mutation Proteolysis Sumoylation |
| description |
Fulvestrant, a selective estrogen receptor down-regulator (SERD) is a pure competitive antagonist of estrogen receptor alpha (ERα). Fulvestrant binds ERα and reduces the receptor's half-life by increasing protein turnover, however, its mechanism of action is not fully understood. In this study, we show that removal of the ERα nuclear localization sequence (ERδNLS) resulted in a predominantly cytoplasmic ERα that was degraded in response to 17-β-estradiol (E2) but was resistant to degradation by fulvestrant. ERδNLS bound the ligands and exhibited receptor interaction similar to ERα, indicating that the lack of degradation was not due to disruption of these processes. Forcing ERδNLS into the nucleus with a heterologous SV40-NLS did not restore degradation, suggesting that the NLS domain itself, and not merely receptor localization, is critical for fulvestrant-induced ERα degradation. Indeed, cloning of the endogenous ERα NLS onto the N-terminus of ERδNLS significantly restored both its nuclear localization and turnover in response to fulvestrant. Moreover, mutation of the sumoylation targets K266 and K268 within the NLS impaired fulvestrant-induced ERα degradation. In conclusion, our study provides evidence for the unique role of the ERα NLS in fulvestrant-induced degradation of the receptor. © 2015 Elsevier Ireland Ltd. |
| format |
JOUR |
| author |
Casa, A.J. Hochbaum, D. Sreekumar, S. Oesterreich, S. Lee, A.V. |
| author_facet |
Casa, A.J. Hochbaum, D. Sreekumar, S. Oesterreich, S. Lee, A.V. |
| author_sort |
Casa, A.J. |
| title |
The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor |
| title_short |
The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor |
| title_full |
The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor |
| title_fullStr |
The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor |
| title_full_unstemmed |
The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor |
| title_sort |
estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor |
| url |
http://hdl.handle.net/20.500.12110/paper_03037207_v415_n_p76_Casa |
| work_keys_str_mv |
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