Dimerization of mammalian progesterone receptors occurs in the absence of DNA and is related to the release of the 90-kDa heat shock protein.

DeMarzo, Angelo M.; Beck, Candace A.; Oñate, Sergio A.; Edwards, Dean P.

doi:10.1073/pnas.88.1.72

Cited by 112 publications

(64 citation statements)

References 25 publications

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“…Oligomerization, most commonly dimerization, of monomeric protein units is a common mechanism for expanding the regulatory potential of individual gene products (3,7,8,11,22). Dimerization results from interaction between structural domains within protein monomers that are distinct from the substrate binding or catalytic domains.…”

Section: Discussionmentioning

confidence: 99%

Control of fibroblast growth factor receptor kinase signal transduction by heterodimerization of combinatorial splice variants.

Shi¹,

Kan²,

Xu³

et al. 1993

Mol. Cell. Biol.

117

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A differentiated liver cell (HepG2), which exhibits a dose-dependent growth-stimulatory and growthinhibitory response to heparin-binding fibroblast growth factor type 1 (FGF-1), displays high-and low-affinity receptor phenotypes and expresses specific combinatorial splice variants al, f1, and a2 of the FGF receptor (FGF-R) gene (flg). The extracellular domains of the a and 13 variants consist of three and two immunoglobulin loops, respectively, while the intracellular variants consist of a tyrosine kinase (type 1) isoform and a kinase-defective (type 2) isoform. The type 2 isoform is also devoid of the two major intracellular yrosine autophosphorylation sites Heparin-binding fibroblast growth factors (FGF) elicit dose-dependent growth-stimulatory and growth-inhibitory effects in cells which display high-and low-affinity receptor sites (23, 24). The FGF receptor (FGF-R) tyrosine kinase family consists of splice variants in the extracellular ligandbinding domains which combine with splice variants in the intracellular kinase, autophosphorylation, and substrate interaction domains (17). Transmembrane tyrosine kinase receptors are activated by a ligand-induced stabilization of dimers which occurs through the receptor extracellular domain (15,44,46,50,51). Kinase-defective mutants in the intracellular domain act as dominant negative suppressors of ligand-induced biological activities when coexpressed with wild-type receptors (1,28,42,44,45). This is thought to result from competition with the formation of kinase homodimers and prevention of the intermolecular trans phosphorylation of tyrosines within monomeric units of kinase homodimers which is obligatory for binding, phosphorylation, and activation of signal transduction substrates con-* Corresponding author. taining src homology region 2 (SH2) domains (4,15,16,28,30,43). Alternate splicing of an exon coding for an NH2-terminal immunoglobulin-like disulfide loop results in isoforms in the extracellular domain of FGF-R composed of three (a isoform) and two (1 isoform) immunoglobulin loops (17). Although the two immunoglobulin loops that compose the 1 isoform are qualitatively sufficient for ligand binding, the NH2-terminal loop of the three-loop a isoform is interactive with the two-loop ligand-binding site (47). In liver cells which exhibit the inhibitory response to FGF-1, an alternate donor site splice results in a kinase-defective COOH-terminal isoform (type 2) that is devoid of the complete catalytic domain and the two major intracellular tyrosine autophosphorylation sites (Tyr-653 and Tyr-766) of the intact type 1 kinase (17, 18). Phosphotyrosine 766 is required for interaction of the FGF-R kinase with the SH2 domain signal transduction substrate, phospholipase C-yl (PLC-yl) (32,33,35

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Section: Discussionmentioning

confidence: 99%

Control of fibroblast growth factor receptor kinase signal transduction by heterodimerization of combinatorial splice variants.

Shi¹,

Kan²,

Xu³

et al. 1993

Mol. Cell. Biol.

117

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“…Dimerization of the estrogen receptor may thus be a prerequisite for its high-affinity binding to specific DNA sequences. Moreover, evidence has also been provided that the association constant for dimerization [39] and the stability of the dimers [23] are relatively low for the progesterone receptor, especially when compared with the estrogen receptor [ 391.…”

Section: Discussionmentioning

confidence: 99%

“…the specific PRE used or to the method used for the study of receptor-DNA interactions. The gel-shift method has been used in numerous studies of receptor dimerization [3,5,6,[19][20][21][22][23][24][25][26][27]. We thus used this method to compare the binding of purified wild-type and constitutive mutant progesterone receptors to isolated PRE, either to the BSI element of MMTV or to a synthethic PRE corresponding to the palindromic consensus sequence [28].…”

Section: Comparison Of the Binding Of Wild-type And Constitutive Mutamentioning

confidence: 99%

Specific binding of progesterone receptor to progesterone‐responsive elements does not require prior dimerization

Cohen‐Solal

Bailly

Rauch

et al. 1993

European Journal of Biochemistry

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Steroid-hormone receptors undergo, prior to binding to DNA, a hormone-dependent dimerization. It is generally accepted that this dimerization is indispensable for the high-affinity binding of hormone receptor to hormone-responsive elements.Using a progesterone-receptor mutant with the complete steroid-binding domain deleted (positions 663 -930), with or without the epitope required for binding the monoclonal antibody Let 126, we have shown that this receptor species was unable to undergo dimerization in solution. However, this mutant retained a high affinity (60-70% of the affinity of the wild-type receptor) for the progesterone-responsive elements of the mouse-mammary-tumor-virus long-terminal-repeat promoter and for a consensus palindromic. progesterone-responsive element, as measured by both DNase-I protection experiments and gel-shift experiments. This mutant also increased gene transcription. Thus, at least in the case of the progesterone receptor, prior dimerization is dispensable for receptor binding to regulatory DNA elements and for subsequent transcription activation.

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“…However, glucocorticoid receptor (GR [6]), progesterone receptor (PR [8]), and estrogen receptor (ER [9]) can dimerize in the absence of DNA, so the presence of two half-sites in some specific juxtaposition is not an obligatory requirement for dimerization. This has been demonstrated most directly for GR, where crystallographic studies reveal that a dimer of the GR DNA-binding domain binds to a glucocorticoid response element half-site.…”

Section: Discussionmentioning

confidence: 99%

Activation of the phosphoenolpyruvate carboxykinase gene retinoic acid response element is dependent on a retinoic acid receptor/coregulator complex.

Hall¹,

Scott²,

Noisin³

et al. 1992

Mol. Cell. Biol.

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The accessory factor 1 (AF1) element is an upstream transcriptional control region that plays a role in the response of the phosphoenolpyruvate carboxykinase (PEPCK) gene to both glucocorticoids and retinoic acid. We demonstrate here that retinoic acid receptor alpha (RARa) binds to a sequence within the AF1 element, TGACCT (site B), that is a consensus retinoic acid response element (RARE) half-site. A similar DNA sequence, TGGCCG (site C), located 1 bp downstream of site B, is not involved in the binding of RARa monomers or dimers but is required for the constitution of a functional RARE. Site C is also required for the formation of a complex invohling RARa and a liver nuclear factor designated CR, for coregulator. Mutational analysis of the AF1 element shows that the RARcv/CR complex is the trans-acting unit that mediates the retinoic acid response of the PEPCK gene. Another member of the retinoid receptor family, retinoid X receptor alpha (RXRa), can also form a complex with RARa and the AF1 element. Several observations, including the observation that RXRa antibody interacts with CR, indicate that RXRa and CR are identical or closely related proteins. Though RXRa forms a complex with RARa and the AF1 element, we demonstrate that the AF1 element is functionally distinguishable from a retinoid X response element. Taken together, our results show that the AF1 element contains an RARE that mediates a retinoic acid response by binding an RARv/ coregulator complex; this coregulator is presumably RXRa.The effects of the steroid/thyroid/retinoid family of hormones on gene expression are mediated by intracellular receptors that bind to their cognate hormone response elements in target genes (2,11,14,45,47). The half-sites that compose these hormone response elements differ in their primary sequence and arrangement (33). Response elements for estrogen, vitamin D, thyroid hormone, and retinoic acid are composed of two or more similar copies of the consensus half-site sequence TGACCT arranged as either palindromic or direct repeats (33). The spacing of the half-sites relative to each other is a critical parameter that is, at least in part, responsible for determining which receptor binds to a given response element and mediates a hormone response (35,46 (GRU [19]; for a review, see reference 16). Deletion of the AF1 element results in a 50% reduction in the PEPCK glucocorticoid response (19) and an even greater reduction in the retinoic acid response (28). Thus, the AF1 element plays a critical role in two distinct hormone responses.RARa binds to the AF1 element and forms two retarded complexes in a gel shift assay (28). These two complexes represent the interaction of monomeric and dimeric forms of RARa with the AF1 element (27). Mutational analysis, combined with gel mobility shift assays, showed that a consensus RARE half-site (TGACCT, site B [the nucleotide boundaries of site B in this work correspond to those of site B in reference 28]) within the AF1 element is critical for binding of RARa (28). Site B and a simi...

show abstract

Dimerization of mammalian progesterone receptors occurs in the absence of DNA and is related to the release of the 90-kDa heat shock protein.

Cited by 112 publications

References 25 publications

Control of fibroblast growth factor receptor kinase signal transduction by heterodimerization of combinatorial splice variants.

Control of fibroblast growth factor receptor kinase signal transduction by heterodimerization of combinatorial splice variants.

Specific binding of progesterone receptor to progesterone‐responsive elements does not require prior dimerization

Activation of the phosphoenolpyruvate carboxykinase gene retinoic acid response element is dependent on a retinoic acid receptor/coregulator complex.

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