Interaction of the chicken progesterone receptor with heat shock protein (HSP) 90

Carson-Jurica, M.A.; Lee, A.T.; Dobson, Alan D. W.; Conneely, Orla M.; Schrader, William T.; O’Malley, Bert W.

doi:10.1016/0022-4731(89)90060-5

Cited by 47 publications

(13 citation statements)

References 31 publications

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“…Ligand binding causes a dissociation of this complex and release of an activated receptor which now binds to DNA. This model is supported by observations that the glucocorticoid, progesterone, and estrogen receptors, when extracted from cells in the absence of hormone and in low salt, exist in large complexes composed of receptors, HSP90, and HSP70 (5)(6)(7)(8)(9)(10)36). Such complexes can be dissociated in vitro by the addition of hormone, producing a form of the receptor that is capable of binding DNA (2).…”

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confidence: 57%

In situ distinction between steroid receptor binding and transactivation at a target gene.

1991

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We have developed a DNA interference assay in the yeast Saccharomyces cerevisiae that is designed to indicate the intracellular DNA-binding status of the estrogen receptor. The assay utilizes a promoter containing multiple copies of a GAL4-estrogen receptor binding sequence. This element is designed so that either an estrogen receptor or a GAL4 molecule, but not both, can occupy it simultaneously. The assay is extremely sensitive, and at concentrations of estrogen receptor below that required for maximal transcriptional activation of its target estrogen response element, a quantitative inhibition of (3,8,15,20,30,41). Structurally, these molecules are similar, consisting of well-defined DNA and hormone binding domains and other less well defined activation domains that presumably mediate the interaction of receptors with the transcription apparatus (12,15,39). The mechanisms of activation of these transactivators are related, since ligand binding is required for converting these receptors from an inactive to an active form in vivo (8,15,20 A second model of activation suggests that a receptor is always bound to its response element and that the role of hormone is to convert it into a transcriptionally active form, possibly by displacing an inhibitory protein or directing an allosteric or covalent modification. This is analogous to the mechanism by which galactose regulates the binding of the GAL80 inhibitor to the GAL4 transactivator (23). In support of this model are the in vitro observations that retinoic acid receptor, thyroid hormone receptor, and estrogen receptor bind to DNA constitutively in the absence of hormone (4,18,19,26,39). Recent reports have suggested that the estrogen receptor is constitutively bound to its response element in vivo (40). Furthermore, it has been suggested that the bound receptor may possess ligand-independent activating and repressor activities. In fact, since progesterone receptor can be converted to an active form by mild heat treatment, it has been suggested that at body temperature, all of the progesterone receptor could be activated and constitutively bound to DNA (42).Finally, questions remain as to whether ligand-induced DNA-binding capacity can be separated from transactivation activity for a steroid receptor. Clearly there is an element of confusion as to the form of the receptor prior to transformation and the role of ligand in this process. It is quite possible that a single model will not explain the mode of action of all receptors and that the steps of activation must be elucidated for each receptor. In this study, we use a reconstituted estrogen-responsive system in Saccharomyces cerevisiae to examine the interaction of estrogen receptor with its response element in situ and the role of ligand in this association. The yeast system has been shown by several groups to be a representative model for steroid hormone action (27)(28)(29)34). S. cerevisiae was chosen for this study because of the absolute requirement for estrogen for gene activation by this receptor in ...

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confidence: 57%

In situ distinction between steroid receptor binding and transactivation at a target gene.

1991

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“…and the DBD and contains additional trans-activation functions together with sequences required for stabilization of interaction of inactive receptors with heat shock proteins (Dobson et al 1989;Carson-Jurica et al 1990a). The amino-terminal region of the PR, which is the most hypervariable region in terms of both size and sequence among members of this superfamily, contains trans-activation functions that modulate both the level and promoter specificity of target gene activation (Tora et al 1988;Sartorius et al 1994).…”

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confidence: 99%

Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.

Lydon¹,

DeMayo²,

Funk³

et al. 1995

Genes Dev.

1,698

1,242

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Although progesterone has been recognized as essential for the establishment and maintenance of pregnancy, this steroid hormone has been recently implicated to have a functional role in a number of other reproductive events. The physiological effects of progesterone are mediated by the progesterone receptor (PR), a member of the nuclear receptor superfamily of transcription factors. In most cases the PR is induced by estrogen, implying that many of the in vivo effects attributed to progesterone could also be the result of concomitantly administered estrogen. Therefore, to clearly define those physiological events that are specifically attributable to progesterone in vivo, we have generated a mouse model carrying a null mutation of the PR gene using embryonic stem cell/gene targeting techniques. Male and female embryos homozygous for the PR mutation developed normally to adulthood. However, the adult female PR mutant displayed significant defects in all reproductive tissues. These included an inability to ovulate, uterine hyperplasia and inflammation, severely limited mammary gland development, and an inability to exhibit sexual behavior. Collectively, these results provide direct support for progesterone's role as a pleiotropic coordinator of diverse reproductive events that together ensure species survival.

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“…The inactive cytoplasmic forms of the glucocorticoid (18 [and references within], 35), estrogen (7 [and references within]), progesterone (6), and aryl hydrocarbon (AH) (29) receptors exist as stable complexes containing HSP90, whereas the ligand-activated nuclear forms lack HSP90. HSP90 is thought to negatively regulate activation and translocation of the cytoplasmic forms of the receptors in the absence of ligand (1).…”

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confidence: 99%

Conformational activation of a basic helix-loop-helix protein (MyoD1) by the C-terminal region of murine HSP90 (HSP84).

1992

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A murine cardiac Agtll expression library was screened with an amphipathic helix antibody, and a recombinant representing the C-terminal 194 residues of murine HSP90 (HSP84) was cloned. Both recombinant and native HSP9Os were then found to rapidly convert a basic helix-loop-helix protein (MyoDi) from an inactive to an active conformation, as assayed by sequence-specific DNA binding. The conversion process involves a transient interaction between HSP9O and MyoDl and does not result in the formation of a stable tertiary complex. Conversion does not require ATP and occurs stoichiometrically in a dose-dependent fashion.HSP90 is an abundant, ubiquitous, and highly conserved protein present in most eukaryotic cells. These results provide direct evidence that HSP90 can affect the conformational structure of a DNA-binding protein.Heat shock proteins (HSPs) are thought to aid cells coping with stress, and their expression is induced by heat, heavy metals, pH, and alcohol (reviewed in references 13 and 16). Recent studies have shown that some classes of HSP (HSP60 and HSP70) also function in membrane translocation and folding of proteins in cells that are not under stress (reviewed in reference 13). Synthesis of HSP90 increases in some cells three to fivefold under stress conditions, but it is also abundant in uninduced cells (22). Most of the information acquired so far about the function of HSP90 has been through association, and an activity for the protein has not been described in vitro. HSP90 interacts with several viral oncogene products that display tyrosine kinase activity (4,25,31,39), associates with tubulin and actin (28, 36), stimulates the activity of eukarytotic initiation factor 2 a subunit-specific protein kinase (33), and forms stable complexes with some members of the nuclear receptor superfamily (see below). Sequence analysis has shown that HSP90 (the generic name for this family used here) is highly conserved among species (summarized in reference 15): human (HSP90), mouse (HSP84), chicken (HSP90), Drosophila (HSP83), Trypanosoma (HSP85), and yeast (HSP83) homologs display a minimum of 65% amino acid conservation.Members of the nuclear receptor superfamily display DNA-binding activity and translocate from the cytoplasm to the nucleus after acquiring a ligand. The inactive cytoplasmic forms of the glucocorticoid (18 [and references within], 35), estrogen (7 [and references within]), progesterone (6), and aryl hydrocarbon (AH) (29) receptors exist as stable complexes containing HSP90, whereas the ligand-activated nuclear forms lack HSP90. HSP90 is thought to negatively regulate activation and translocation of the cytoplasmic forms of the receptors in the absence of ligand (1). Substantial evidence suggests that binding of HSP90 may be essential to the subsequent activity of these receptors and that HSP90 may be involved in their initial folding. Glucocorticoid receptor translated from a reticulocyte lysate, which * Corresponding author.contains HSP90, displayed high-affinity hormone-binding activity, whe...

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Interaction of the chicken progesterone receptor with heat shock protein (HSP) 90

Cited by 47 publications

References 31 publications

In situ distinction between steroid receptor binding and transactivation at a target gene.

In situ distinction between steroid receptor binding and transactivation at a target gene.

Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.

Conformational activation of a basic helix-loop-helix protein (MyoD1) by the C-terminal region of murine HSP90 (HSP84).

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