Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor

Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation withi...

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Autores principales:	Presman, Diego Martín, Ogara, Maria Florencia, Burton, Gerardo, Levi, Valeria, Pecci, Adali
Publicado:	2014
Materias:	Animals Cells, Cultured DNA Mice Protein Multimerization Protein Structure, Tertiary Receptors, Glucocorticoid
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15449173_v12_n3_p_Presman http://hdl.handle.net/20.500.12110/paper_15449173_v12_n3_p_Presman
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_15449173_v12_n3_p_Presman
record_format	dspace
spelling	paper:paper_15449173_v12_n3_p_Presman2023-06-08T16:21:10Z Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor Presman, Diego Martín Ogara, Maria Florencia Burton, Gerardo Levi, Valeria Pecci, Adali Animals Cells, Cultured DNA Mice Protein Multimerization Protein Structure, Tertiary Receptors, Glucocorticoid Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation within the GR DNA-binding domain (GRdim mutant) has been reported as crucial for receptor dimerization and DNA binding, this assumption has recently been challenged. Here we have analyzed the GR oligomerization state in vivo using the number and brightness assay. Our results suggest a complete, reversible, and DNA-independent ligand-induced model for GR dimerization. We demonstrate that the GRdim forms dimers in vivo whereas adding another mutation in the ligand-binding domain (I634A) severely compromises homodimer formation. Contrary to dogma, no correlation between the GR monomeric/dimeric state and transcriptional activity was observed. Finally, the state of dimerization affected DNA binding only to a subset of GR binding sites. These results have major implications on future searches for therapeutic glucocorticoids with reduced side effects. © 2014. Fil:Presman, D.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Ogara, M.F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Levi, V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15449173_v12_n3_p_Presman http://hdl.handle.net/20.500.12110/paper_15449173_v12_n3_p_Presman
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Animals Cells, Cultured DNA Mice Protein Multimerization Protein Structure, Tertiary Receptors, Glucocorticoid
spellingShingle	Animals Cells, Cultured DNA Mice Protein Multimerization Protein Structure, Tertiary Receptors, Glucocorticoid Presman, Diego Martín Ogara, Maria Florencia Burton, Gerardo Levi, Valeria Pecci, Adali Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor
topic_facet	Animals Cells, Cultured DNA Mice Protein Multimerization Protein Structure, Tertiary Receptors, Glucocorticoid
description	Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation within the GR DNA-binding domain (GRdim mutant) has been reported as crucial for receptor dimerization and DNA binding, this assumption has recently been challenged. Here we have analyzed the GR oligomerization state in vivo using the number and brightness assay. Our results suggest a complete, reversible, and DNA-independent ligand-induced model for GR dimerization. We demonstrate that the GRdim forms dimers in vivo whereas adding another mutation in the ligand-binding domain (I634A) severely compromises homodimer formation. Contrary to dogma, no correlation between the GR monomeric/dimeric state and transcriptional activity was observed. Finally, the state of dimerization affected DNA binding only to a subset of GR binding sites. These results have major implications on future searches for therapeutic glucocorticoids with reduced side effects. © 2014.
author	Presman, Diego Martín Ogara, Maria Florencia Burton, Gerardo Levi, Valeria Pecci, Adali
author_facet	Presman, Diego Martín Ogara, Maria Florencia Burton, Gerardo Levi, Valeria Pecci, Adali
author_sort	Presman, Diego Martín
title	Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor
title_short	Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor
title_full	Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor
title_fullStr	Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor
title_full_unstemmed	Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor
title_sort	live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor
publishDate	2014
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15449173_v12_n3_p_Presman http://hdl.handle.net/20.500.12110/paper_15449173_v12_n3_p_Presman
work_keys_str_mv	AT presmandiegomartin livecellimagingunveilsmultipledomainrequirementsforinvivodimerizationoftheglucocorticoidreceptor AT ogaramariaflorencia livecellimagingunveilsmultipledomainrequirementsforinvivodimerizationoftheglucocorticoidreceptor AT burtongerardo livecellimagingunveilsmultipledomainrequirementsforinvivodimerizationoftheglucocorticoidreceptor AT levivaleria livecellimagingunveilsmultipledomainrequirementsforinvivodimerizationoftheglucocorticoidreceptor AT pecciadali livecellimagingunveilsmultipledomainrequirementsforinvivodimerizationoftheglucocorticoidreceptor
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Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor

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