Document Detail


Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins.
MedLine Citation:
PMID:  18771283     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The TPR proteins FKBP52, FKBP51, Cyp40, and PP5 are found in steroid receptor (SR) complexes, but their receptor-specific preferences and roles remain unresolved. We have undertaken a systematic approach to this problem by examining the contribution of all four TPRs to the localization properties of glucocorticoid (GR) and progesterone (PR) receptors. The GR of L929 cells was found in the cytoplasm in a complex containing PP5 and FKBP51, while the GR of WCL2 cells was nuclear and contained PP5 and FKBP52. Cyp40 did not interact with the GR in either cell line. To test whether FKBP interaction determined localization, we overexpressed Flag-tagged FKBP51 in WCL2 cells and Flag-FKBP52 in L929 cells. In WCL2 cells, the GR exhibited a shift to greater cytoplasmic localization that correlated with recruitment of Flag-FKBP51. In contrast, Flag-FKBP52 was not recruited to the GR of L929 cells, and no change in localization was observed, suggesting that both cell-type-specific mechanisms and TPR abundance contribute to the SR-TPR interaction. As a further test, GR-GFP and PR-GFP constructs were expressed in COS cells. The GR-GFP construct localized to the cytoplasm, while the PR-GFP construct was predominantly nuclear. Similar to L929 cells, the GR in COS interacted with PP5 and FKBP51, while PR interacted with FKBP52. Analysis of GR-PR chimeric constructs revealed that the ligand-binding domain of each receptor determines both TPR specificity and localization. Lastly, we analyzed GR and PR localization in cells completely lacking TPR. PR in FKBP52 KO cells showed a complete shift to the cytoplasm, while GR in FKBP51 KO and PP5 KO cells showed a moderate shift to the nucleus, indicating that both TPRs contribute to GR localization. Our results demonstrate that SRs have distinct preferences for TPR proteins, a property that resides in the LBD and which can now explain long-standing differences in receptor subcellular localization.
Authors:
Ananya Banerjee; Sumudra Periyasamy; Irene M Wolf; Terry D Hinds; Weidong Yong; Weinian Shou; Edwin R Sanchez
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-09-05
Journal Detail:
Title:  Biochemistry     Volume:  47     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-09-24     Completed Date:  2008-12-01     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10471-80     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites
COS Cells
Cell Adhesion
Cercopithecus aethiops
Fibroblasts / cytology,  physiology
Haplorhini
L Cells (Cell Line)
Ligands
Mice
Oligopeptides / chemistry*,  metabolism*
Receptors, Glucocorticoid / chemistry,  metabolism*
Receptors, Progesterone / chemistry,  metabolism*
Recombinant Fusion Proteins / chemistry,  metabolism
Repetitive Sequences, Amino Acid
Subcellular Fractions / metabolism
Tacrolimus Binding Proteins / metabolism
Grant Support
ID/Acronym/Agency:
DK43867/DK/NIDDK NIH HHS; DK70127/DK/NIDDK NIH HHS; DK73402/DK/NIDDK NIH HHS; F31 DK084958-01A1/DK/NIDDK NIH HHS; F31 DK084958-02/DK/NIDDK NIH HHS; R01 DK043867-09/DK/NIDDK NIH HHS; R01 DK070127-04/DK/NIDDK NIH HHS; R01 DK073402/DK/NIDDK NIH HHS; R01 DK073402-03/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Ligands; 0/Oligopeptides; 0/Receptors, Glucocorticoid; 0/Receptors, Progesterone; 0/Recombinant Fusion Proteins; EC 5.2.1.-/Tacrolimus Binding Proteins
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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