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

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Title: Effects of site specific phosphorylation on the structure and functions of the glucocorticoid receptor
Author: Anna Magdalena Stwora de Garza
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
URI: http : / /hdl .handle .net /2152 .3 /296
Date: 2008-09-04

Citation

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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