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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todo:paper_15449173_v12_n3_p_Presman2023-10-03T16:23:00Z Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor Presman, D.M. Ogara, M.F. Stortz, M. Alvarez, L.D. Pooley, J.R. Schiltz, R.L. Grøntved, L. Johnson, T.A. Mittelstadt, P.R. Ashwell, J.D. Ganesan, S. Burton, G. Levi, V. Hager, G.L. Pecci, A. 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar 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, D.M. Ogara, M.F. Stortz, M. Alvarez, L.D. Pooley, J.R. Schiltz, R.L. Grøntved, L. Johnson, T.A. Mittelstadt, P.R. Ashwell, J.D. Ganesan, S. Burton, G. Levi, V. Hager, G.L. Pecci, A. 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. |
| format |
JOUR |
| author |
Presman, D.M. Ogara, M.F. Stortz, M. Alvarez, L.D. Pooley, J.R. Schiltz, R.L. Grøntved, L. Johnson, T.A. Mittelstadt, P.R. Ashwell, J.D. Ganesan, S. Burton, G. Levi, V. Hager, G.L. Pecci, A. |
| author_facet |
Presman, D.M. Ogara, M.F. Stortz, M. Alvarez, L.D. Pooley, J.R. Schiltz, R.L. Grøntved, L. Johnson, T.A. Mittelstadt, P.R. Ashwell, J.D. Ganesan, S. Burton, G. Levi, V. Hager, G.L. Pecci, A. |
| author_sort |
Presman, D.M. |
| 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 |
| url |
http://hdl.handle.net/20.500.12110/paper_15449173_v12_n3_p_Presman |
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