Inhibition of GR‐mediated transcription by p23 requires interaction with Hsp90

Wochnik, Gabriela M.; Young, Jason C.; Schmidt, Ulrike; Holsboer, Florian; Hartl, F. Ulrich; Rein, Theo

doi:10.1016/s0014-5793(04)00066-3

Cited by 41 publications

(27 citation statements)

References 29 publications

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“…Consistent with our studies of primary embryonic fibroblasts, decreased GR activity secondary to loss of cPGES/p23 would result in loss of this inhibitory pathway, resulting in an increase in PGE 2 and other COX-2-dependent metabolites. Transfection of cell lines with p23 expression vectors has been reported, similar to loss of cPGES/p23, to result in inhibition of GR activity in cells lines (16,73). This raises the possibility that the increased PGE 2 production noted in cells transfected with cPGES/p23 was the indirect consequence of decreased GR function in this line.…”

Section: Discussionmentioning

confidence: 93%

cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E₂ Synthesis

Lovgren

Kovářová

Koller

2007

Molecular and Cellular Biology

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A number of studies have identified cytosolic prostaglandin E 2 synthase (cPGES)/p23 as a cytoplasmic protein capable of metabolism of prostaglandin E 2 (PGE 2 ) from the cyclooxygenase metabolite prostaglandin endoperoxide (PGH 2 ). However, this protein has also been implicated in a number of other pathways, including stabilization of the glucocorticoid receptor (GR) complex. To define the importance of the functions assigned to this protein, mice lacking detectible cPGES/p23 expression were generated. cPGES/p23 ؊/؊ pups die during the perinatal period and display retarded lung development reminiscent of the phenotype of GR-deficient neonates. Furthermore, GR-sensitive gluconeogenic enzymes are not induced in the prenatal period. However, unlike GR-deficient embryos, cPGES/p23 ؊/؊ embryos are small and a proliferation defect is observed in cPGES/p23 ؊/؊ fibroblasts. Analysis of arachidonic acid metabolites in embryonic tissues and primary fibroblasts failed to support a function for this protein in PGE 2 biosynthesis. Thus, while the growth retardation of the cPGES/p23 ؊/؊ pups and decreased proliferation of primary fibroblasts identify functions for this protein in addition to GR stabilization, it is unlikely that these functions include metabolism of PGH 2 to PGE 2 .

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Section: Discussionmentioning

confidence: 93%

cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E₂ Synthesis

Lovgren

Kovářová

Koller

2007

Molecular and Cellular Biology

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“…2A and those using purified recombinant proteins may be due to the fact that p23 can exist in a complex with HSP90 within the cell and that the p23⅐HSP90 complex might interact differently with WT as compared with D4E/C127S PHD2. Previous studies showed that a W106A mutant of p23 is defective in its interaction with HSP90 (34). We therefore tested the role of HSP90-mediated binding by examining the ability of W106A p23 to coimmunoprecipitate PHD2.…”

Section: Resultsmentioning

confidence: 99%

Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

Song

Arsenault

et al. 2014

Journal of Biological Chemistry

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“…Plasmids-The plasmids MTVLuc, green fluorescence protein (GFP)-GR, and pCMV␤-Gal have been described previously (33). All immunophilins and dynamitin were cloned downstream of the CMV promoter of the vector pRK5MCS.…”

Section: Methodsmentioning

confidence: 99%

FK506-binding Proteins 51 and 52 Differentially Regulate Dynein Interaction and Nuclear Translocation of the Glucocorticoid Receptor in Mammalian Cells

Wochnik

Rüegg

Abel

et al. 2005

Journal of Biological Chemistry

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561

495

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We used a cellular system to elucidate the molecular determinants of the large immunophilin FK506-binding proteins (FKBP)51 and -52 for their action on the glucocorticoid receptor in mammalian cells. Increasing the levels of FKBP51 reduced the transcriptional activity of the receptor, as reported. Elevated levels of FKBP52 per se showed no effect but mitigated the inhibition of the receptor induced by FKBP51. We discovered that nuclear translocation of the glucocorticoid receptor was delayed by FKBP51. This correlates with the reduced interaction of FKBP51 with the motor protein dynein compared with FKBP52. From mutational analyses, we concluded that three features of the immunophilins are required for efficient receptor signaling in mammalian cells: hsp90 interaction, dynein association, and peptidylprolyl isomerase (PPIase) enzyme activity. The relevance of dynein for receptor function was substantiated by several experiments: 1) coexpression of dynamitin, which disrupts the transport complex and reduces receptor activity; 2) coexpression of the PPIase domain fragment of FKBP52, which is known to disrupt interaction of the receptor to dynein and reduce glucocorticoid receptor function, in contrast to the corresponding fragment of FKBP51; and 3) swapping of the PPIase domains FKBP51 and FKBP52, which reverses the respective activity. We concluded from our results that the mechanisms of the regulatory system FKBP51/FKBP52 discovered in yeast also operate in mammals to modulate hormone binding of the receptor. In addition, differential regulation of dynein association and nuclear translocation contributes to the effects of the two immunophilins on the glucocorticoid receptor in mammals.

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Inhibition of GR‐mediated transcription by p23 requires interaction with Hsp90

Cited by 41 publications

References 29 publications

cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E₂ Synthesis

cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E₂ Synthesis

Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

FK506-binding Proteins 51 and 52 Differentially Regulate Dynein Interaction and Nuclear Translocation of the Glucocorticoid Receptor in Mammalian Cells

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Inhibition of GR‐mediated transcription by p23 requires interaction with Hsp90

Cited by 41 publications

References 29 publications

cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E2 Synthesis

cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E2 Synthesis

Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

FK506-binding Proteins 51 and 52 Differentially Regulate Dynein Interaction and Nuclear Translocation of the Glucocorticoid Receptor in Mammalian Cells

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Product

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cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E₂ Synthesis

cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E₂ Synthesis