Effects of site specific phosphorylation on the structure and functions of the glucocorticoid receptor

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dc.contributor.advisor Raj Kumar , Ph .D . en_US
dc.contributor.committeeMember Wlodek Bujalowski , Ph .D . en_US
dc.contributor.committeeMember Michael Garabedian , Ph .D . en_US
dc.contributor.committeeMember Golda Leonard , Ph .D . en_US
dc.contributor.committeeMember E . Brad Thompson , M .D . en_US
dc.creator Anna Magdalena Stwora de Garza en_US
dc.date.accessioned 2011 -12 -20T16 :05 :44Z
dc.date.accessioned 2014 -02 -19T22 :05 :50Z
dc.date.available 2010 -09 -28 en_US
dc.date.available 2011 -12 -20T16 :05 :44Z
dc.date.available 2014 -02 -19T22 :05 :50Z
dc.date.created 2008 -12 -18 en_US
dc.date.issued 2008 -09 -04 en_US
dc.identifier.other etd -12182008 -083802 en_US
dc.identifier.uri http : / /hdl .handle .net /2152 .3 /296
dc.description.abstract Ligand dependant transcription factors , like nuclear hormone receptors (NHRs ) , are capable of exerting transcriptional regulation in the nucleus in response to various intra - and extracellular signals . Transcription factors contain segments that are intrinsically disordered (ID ) under native conditions . Posttranslational modifications , such as phosphorylation , affect protein stability and activity of proteins . Conformational changes of such disordered domains have been shown to facilitate binding of one or more coregulatory proteins . The glucocorticoid receptor (GR ) belongs to the NHR super family and contains such an ID domain in its N -terminal region , the AF1 . This transactivation domain must interact with co -regulators for optimal activity and contains most of the conserved phosphorylation sites (S203 , S211 , and S226 ) in the human GR . Published data has linked site -specific phosphorylation of the GR to physiological functions of the GR in a leukemia cell line model (5 ) . This project’s aims were to study how site -specific phosphorylation affects the structure and function of the glucocorticoid receptor . The aims of the project were : 1 ) to test the effect of site -specific phosphorylation on the conformation of the recombinant AF1 domain of the human GR , 2 ) to test the effects of site -specific phosphorylation on the interactions of AF1 with specific coregulatory proteins and the subsequent changes in transcriptional activity in CV -1 cells , and 3 ) to test if site -specific phosphorylation of the GR is controlled by MAPK activity and if this phosphorylation is sufficient to restore lost GR function in refractory hematological malignancies . \r \n We show for the first time , that ID AF1 domain of glucocorticoid receptor (GR ) adopts a functionally folded conformation due to site -specific (S211 ) phosphorylation by p38 MAPK that we have earlier shown to be involved in the apoptotic and gene -inductive events initiated by GR . These conformational changes are important for AF1s interaction with coregulatory proteins , and subsequent GRE mediated transcriptional activity of the GR . \r \n Finally , these conformational changes are important for AF1s interaction with coregulatory proteins , and subsequent GRE mediated transcriptional activity of the GR . This activating phosphorylation , specifically S211 , is controlled by balanced MAPK activity in in vitro cell line models providing and additional mechanism for resistance . Where phosphorylated p38 levels are high relative to low ERK and JNK activity levels . Further suggesting that p38 MAPK activity plays a role in structural and functional consequences of the GR . \r \n en_US
dc.format.medium electronic en_US
dc.language.iso eng en_US
dc.rights Copyright © is held by the author . Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works . en_US
dc.subject phosphorylation en_US
dc.subject MAPK en_US
dc.subject blucocorticoid receptor en_US
dc.title Effects of site specific phosphorylation on the structure and functions of the glucocorticoid receptor en_US
dc.type.genre dissertation en_US
dc.type.material text en_US
thesis.degree.name PhD en_US
thesis.degree.level Doctoral en_US
thesis.degree.grantor The University of Texas Medical Branch en_US
thesis.degree.department Cell Biology en_US

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Effects of site specific phosphorylation on the structure and functions of the glucocorticoid receptor. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /296 .

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