Activation, Transformation, and Subunit Structure of Steroid Hormone Receptors

Grody, Wayne W.; Schrader, William T.; O’Malley, Bert W.

doi:10.1210/edrv-3-2-141

Cited by 317 publications

(38 citation statements)

References 175 publications

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“…Subunit B (105,000 mol wt), which binds to interphase chromosomes (Kd -5 X 10-9 M), has been postulated to play a "specifier" or catalytic role in chromosomal localization of hormone-receptor complex (16). The structural proof and structure-function speculations have been published in detail previously (19,21). It is noteworthy that a similar subunit structure has been reported recently for the progesterone receptor in human cultured cells (22).…”

supporting

confidence: 59%

Steroid hormone action in eucaryotic cells.

O’Malley¹

1984

J. Clin. Invest.

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supporting

confidence: 59%

Steroid hormone action in eucaryotic cells.

O’Malley¹

1984

J. Clin. Invest.

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“…Alopecia is found in affected members of some (7,9,10,12,13,15) but not all (5,6,8,11,14) kindreds; in one patient there was hyperphosphatemia and undetectable levels of 24,25(OH)2D (10); and one patient failed to achieve eucalcemia even with serum 1,25(OH)2D at concentrations 100 times normal for 12 mo. 2 Like the true steroidal hormones, 1,25(OH)2D acts in the nucleus of target cells (16); this requires a multistep process involving hormone receptors, localization of receptor and hormone in the nucleus, and induction of specific messenger RNA synthesis. In theory, resistance to 1,25(OH)2D could arise at any of several points in this process.…”

Section: Introductionmentioning

confidence: 99%

Resistance to 1,25-dihydroxyvitamin D. Association with heterogeneous defects in cultured skin fibroblasts.

Liberman¹,

Eil²,

Marx³

1983

J. Clin. Invest.

118

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A B S T R A C T We evaluated the interaction of [3H]1,25(0H)2D3 with skin fibroblasts cultured from normal subjects or from affected members of six kindreds with rickets and resistance to 1-alpha, 25(OH)2D [1,25(OH)2D]. We analyzed two aspects of the radioligand interaction; nuclear uptake with dispersed, intact cells at 370C and binding at 0C with soluble extract ("cytosol") prepared from cells disrupted in buffer containing 300 mM KCl and 10 mM sodium molybdate.With normal fibroblasts the affinity and capacity of nuclear uptake of [3H]1,25(OH)2D3 were 0.5 nM and 10,300 sites per cell, respectively; for binding with cytosol these were 0.13 nM and 8,900 sites per cell, respectively.The following four patterns of interaction with [3H]1,25(OH)2D3 were observed with cells cultured from affected patients: (a) two kindreds; cytosol binding and whole-cell nuclear uptake both unmeasurable; (b) one kindred, decreased capacity and normal affinity both for binding in cytosol and for nuclear uptake in whole cells; (c) two kindreds, normal or nearly normal capacity and affinity of binding in cytosol but unmeasurable whole-cell nuclear uptake; and (d) one kindred, normal capacity and affinity of both cytosol

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“…At low temperatures, the energydependent nuclear import is prevented, whereas the nuclear export is still functional [Guiochon-Mantel et al 1991]. Cold treatment also stabilizes the oligomeric complex [Grody et al 1982]. It is difficult to study the association in vivo in living cells.…”

confidence: 99%

Evidence for the existence of an oligomeric, non-DNA-binding complex of the progesterone receptor in the cytoplasm

Passinen

Ylikomi²

2009

Eur J Histochem

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Steroid receptors are found as a hetero-oligomeric complex in cell extracts. Due to the dynamic interaction between receptor-associated proteins and receptors, it is difficult to study the oligomeric complex in living cells. Here this was attempted in cells in which the interaction was stabilized by introducing molybdate into the cells or by incubating the cells at low temperature. The complex was studied with an antibody (αD) recognizing only the dissociated form of the chicken progesterone receptor (PR) and with antibodies (PR22, PR6). Recognizing also oligomeric forms of the receptor. When wild-type chicken PR was transfected, all antibodies showed nuclear staining. Molybdate or cold treatment of cells resulted in cytoplasmic accumulation of the PR as detected with PR22/PR6. αD, however, stained predominantly the nuclear PR in treated cells. These findings suggest that when the oligomeric complex of the PR is stabilized in intact cells in vivo and then crosslinked with paraformaldehyde, a portion of the cytoplasmic receptor is seen as an oligomeric complex, whereas, in the nucleus, most, if not all receptor molecules are in dissociated form. Steroid receptors belong to a large family of nuclear receptors functioning as ligand-regulated transcription factors. Receptor function is mediated by receptor-interacting proteins; co-activators interact with agonist-occupied receptors and mediate transcription activation while co-repressors interact with non-liganded or antagonist-occupied and mediate transcription repression. Ligand binding induces a considerable change in the structure of the ligandbinding domain (LBD), affecting the surface exposition of the receptor which dictates the interaction of the cofactors [Moras and Gronemeyer 1998, Renaud et al. 1995, Wurtz et al. 1996. The earliest known receptor-interacting protein is Hsp90 [Dougherty et al. 1984]. It is known to interact in vitro with the LBD of the steroid receptor in a ligand-dependent manner: it binds to non-liganded steroid receptor but not to agonist-occupied receptor. Non-liganded steroid receptor LBDs act as intramolecular repressors of the activation functions of steroid receptors as well as of heterologous proteins when covalently linked to them [Picard et al. 1988]. Deletion of the LBD generates a constitutively active steroid receptor which does not form a stable oligomeric complex with Hsp90 in vitro. In view of these data, it has been proposed that the Hsp90 interaction is responsible for the repressor function of non-liganded LBDs [Scherrer et al. 1993]. Binding of Hsp90 interferes with the DNA binding of the receptor, which has been regarded as one possible mechanism by which Hsp90 functions as a corepressor. Hsp90 is also required for proper ligand binding of the glucocorticoid receptor [Bresnick et al. 1989]. It has been proposed that the oligomeric form of steroid receptors represents a poised conformation, inactive but ready to interact with the ligand. Ligand binding is thought to dissociate the complex and allow receptor binding to ...

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Activation, Transformation, and Subunit Structure of Steroid Hormone Receptors

Cited by 317 publications

References 175 publications

Steroid hormone action in eucaryotic cells.

Steroid hormone action in eucaryotic cells.

Resistance to 1,25-dihydroxyvitamin D. Association with heterogeneous defects in cultured skin fibroblasts.

Evidence for the existence of an oligomeric, non-DNA-binding complex of the progesterone receptor in the cytoplasm

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