Evidence that the modulator of the glucocorticoid-receptor complex is the endogenous molybdate factor.

Bodine, Peter V.N.; Litwack, Gerald

doi:10.1073/pnas.85.5.1462

Cited by 32 publications

(14 citation statements)

References 30 publications

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“…Alternatively, molybdate may mimic the function of other, hsp90-p23 stabilizing factors. The nature of these putative factor(s) stabilizing the interaction between p23 and hsp90 is presently unknown, but it may be a protein, possibly a chaperone, or a different type of agent such as the glucocorticoid receptor stabilizing factor modulator (45)(46)(47). Clearly, the precise role of ligand in dioxin receptor activation and the possible involvement of novel factors in this process needs to be further elucidated.…”

Section: Discussionmentioning

confidence: 99%

Evidence That the Co-chaperone p23 Regulates Ligand Responsiveness of the Dioxin (Aryl Hydrocarbon) Receptor

Kazlauskas

Poellinger

Pongratz

1999

Journal of Biological Chemistry

241

164

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The dioxin (aryl hydrocarbon) receptor is a ligand-dependent transcription factor that induces expression of a number of genes encoding drug metabolizing enzymes. In the absence of ligand the dioxin receptor is present in the cytoplasmic compartment of the cell associated with the molecular chaperone hsp90, which has been implicated in regulating the correct folding of the ligand binding domain of the receptor. In this study we have examined a potential role of the hsp90-associated p23 protein in the activation process of the dioxin receptor to a DNA binding form. In an in vitro model we show that addition of ligand alone to the dioxin receptor fails to induce release of hsp90 from the dioxin receptor. In the presence of ligand, this release was, however, induced upon addition of purified preparations of Arnt. Interestingly, p23 was also found to be associated with the nonactivated form of the dioxin receptor. Following fractionation on sucrose gradients p23 was dissociated from the receptor-hsp90 complex generating a receptor form, which showed ligand-independent release of hsp90 by Arnt and, consequently, ligand-independent activation of the DNA binding activity of the dioxin receptor. Ligand dependence was reconstituted in the presence of molybdate, a transition metal ion known to stabilize the interaction between the molecular chaperone hsp90 and p23. Taken together these experiments suggest a role of p23 in modulating ligand responsiveness in the activation process of the dioxin receptor.The bHLH-PAS dioxin (aryl hydrocarbon) 1 receptor (1, 2) is a member of a growing family of transcription factors that includes, among others, a number of circadian rhythmicity regulatory proteins (3, 4) and proteins such as the hypoxia-inducible factor HIF-1␣ (5), its endothelial cell-specific homologue E-PAS/HLF (6, 7), and Arnt (8), which is a partner factor both of the dioxin receptor and of hypoxia-inducible factors. These factors, with the possible exception of Arnt, appear to be conditionally regulated and respond to different stimuli. The dioxin receptor is activated by dioxin (9) and related environmental pollutants, whereas HIF 1␣ is activated under conditions of oxygen deprivation to induce the expression of genes encoding, e.g. erythropoietin and vascular endothelial growth factor (10).In the absence of ligand the dioxin receptor is present in a latent conformation in the cytoplasmic compartment of the cell (11) associated with the molecular chaperone hsp90 (12). Hsp90 is required both for maintaining the dioxin receptor in a latent non-DNA binding state and a ligand binding conformation (13). Expression of the dioxin receptor in mutant yeast cells containing reduced levels of hsp90 abolishes ligand responsiveness demonstrating the critical importance of hsp90 for dioxin receptor function (14, 15). The nuclear form of the dioxin receptor interacts with Arnt (16 -18) and does no longer posses the ability to bind ligand and does not interact with the molecular chaperone hsp90 (12,13). This form of the receptor spe...

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Section: Discussionmentioning

confidence: 99%

Evidence That the Co-chaperone p23 Regulates Ligand Responsiveness of the Dioxin (Aryl Hydrocarbon) Receptor

Kazlauskas

Poellinger

Pongratz

1999

Journal of Biological Chemistry

241

164

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“…The differences in the endogenous modulators of GR functioning at two different phases of life span and/or alterations in the physicochemical properties of GRs might play a role in lowering the activation in older mice. 52 Lowtemperature Ca 2+ -dependent activation of the H-R complexes was more pronounced than temperature-mediated activation in the kidney of older animals. The exact mechanisms for this activation are not well understood.…”

Section: Discussionmentioning

confidence: 90%

“…A significant decrease (15–20%) was observed in the magnitude of activation in renal GR in old animals compared to the adult animals in the AL‐fed mice. The differences in the endogenous modulators of GR functioning at two different phases of life span and/or alterations in the physicochemical properties of GRs might play a role in lowering the activation in older mice 52 . Low‐temperature Ca 2+ ‐dependent activation of the H–R complexes was more pronounced than temperature‐mediated activation in the kidney of older animals.…”

Section: Discussionmentioning

confidence: 98%

Age‐Dependent Decrease in Renal Glucocorticoid Receptor Function Is Reversed by Dietary Restriction in Mice

Sharma

Dutta

2006

Annals of the New York Academy of Sciences

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The effects of age and dietary restriction (alternate days of feeding for 3 months) on the concentration, activation, and DNase I digestion of nuclear-bound glucocorticoid receptors (GRs) in the kidney of male mice at two different ages (5 months as adult and 20 months as old) were investigated. A significant decrease (30%) in the concentration of renal GRs was observed in older ad libitum (AL)-fed mice as compared to the adult mice. Dietary restriction (DR) of older mice significantly increased (28%) the level of GRs as compared to the AL-fed control animals. The affinity of the receptor for the hormone remained the same for both AL- and DR-fed animals at both ages. Scatchard and slot blot analyses of the data confirmed the decreased level of renal GRs in older mice compared to the adult mice as well as an increased level of receptor in older DR mice. Activation studies of GRs by both salt and heat indicated a decreased (15-20%) activation of renal GRs in older animals compared to the adult mice in the AL-fed group. It was further observed that DR significantly enhanced (30%) the degree of both salt- and heat-dependent activation of GRs in older animals compared to the AL-fed animals of the age-matched group. DNase I digestion and extraction of nuclear-bound GR complexes showed a lower degree (26%) of extraction in older AL-fed animals compared to the adult animals. However, DR did not alter the pattern of digestibility of bound GR complexes. These above findings indicate that DR could reverse the decrease of GR function in older animals and may provide better adaptability of kidney in water and electrolyte balance.

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“…Testosterone [1,2,6,7,16, H(N)] (102 Ci/mmol) for androgen binding and inhibition assays was acquired from NEN Life Science Products (Germany), DNase I (from bovine pancreas: Sigma (# D 0751), Germany), RNase A (bovine pancreas: Sigma (# R 5503), Germany), trypsin (bovine pancreas, TPCK-treated: Merck (# 124581), Germany), trypsin-inhibitor (soybean: Merck (# 124020), Germany), phospholipase A2 (bee venom (Apis melifera): Fluka, Germany), phospholipase C (Bacillus cereus: Sigma (# P 4014), Germany).…”

Section: Methodsmentioning

confidence: 99%

A Low-Molecular-Weight Cytosolic Inhibitor of the Specific Testosterone Binding in Bovine Seminal Vesicles

Oberste-Frielinghaus

Bürger

Rapior

et al. 2000

Biochemical and Biophysical Research Communications

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Evidence that the modulator of the glucocorticoid-receptor complex is the endogenous molybdate factor.

Cited by 32 publications

References 30 publications

Evidence That the Co-chaperone p23 Regulates Ligand Responsiveness of the Dioxin (Aryl Hydrocarbon) Receptor

Evidence That the Co-chaperone p23 Regulates Ligand Responsiveness of the Dioxin (Aryl Hydrocarbon) Receptor

Age‐Dependent Decrease in Renal Glucocorticoid Receptor Function Is Reversed by Dietary Restriction in Mice

A Low-Molecular-Weight Cytosolic Inhibitor of the Specific Testosterone Binding in Bovine Seminal Vesicles

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