Publications by authors named "Piia Aarnisalo"

16 Publications

  • Page 1 of 1

Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy.

J Biol Chem 2016 Jan 23;291(4):1631-1642. Epub 2015 Nov 23.

From the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114,; Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305,. Electronic address:

Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including Gsα. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of Gsα in the osteoblast lineage. Postnatal removal of Gsα in the osteoblast lineage (P-Gsα(OsxKO) mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1-34) (80 μg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-Gsα(OsxKO) mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-Gsα(OsxKO) mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via Gsα but not phospholipase C via Gq/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of Gsα in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond Gsα and Gq/11 act downstream of PTH on osteoblast differentiation.
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http://dx.doi.org/10.1074/jbc.M115.679753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722446PMC
January 2016

Loss of Gsα early in the osteoblast lineage favors adipogenic differentiation of mesenchymal progenitors and committed osteoblast precursors.

J Bone Miner Res 2014 Nov;29(11):2414-26

Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.

In humans, aging and glucocorticoid treatment are associated with reduced bone mass and increased marrow adiposity, suggesting that the differentiation of osteoblasts and adipocytes may be coordinately regulated. Within the bone marrow, both osteoblasts and adipocytes are derived from mesenchymal progenitor cells, but the mechanisms guiding the commitment of mesenchymal progenitors into osteoblast versus adipocyte lineages are not fully defined. The heterotrimeric G protein subunit Gs α activates protein kinase A signaling downstream of several G protein-coupled receptors including the parathyroid hormone receptor, and plays a crucial role in regulating bone mass. Here, we show that targeted ablation of Gs α in early osteoblast precursors, but not in differentiated osteocytes, results in a dramatic increase in bone marrow adipocytes. Mutant mice have reduced numbers of mesenchymal progenitors overall, with an increase in the proportion of progenitors committed to the adipocyte lineage. Furthermore, cells committed to the osteoblast lineage retain adipogenic potential both in vitro and in vivo. These findings have clinical implications for developing therapeutic approaches to direct the commitment of mesenchymal progenitors into the osteoblast lineage.
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http://dx.doi.org/10.1002/jbmr.2270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220542PMC
November 2014

Gsα enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice.

J Clin Invest 2011 Sep 1;121(9):3492-504. Epub 2011 Aug 1.

Endocrine Unit, Massachusetts General Hospital, 50 Blossom Street, Boston, Massachusetts 02114, USA.

The heterotrimeric G protein subunit Gsα stimulates cAMP-dependent signaling downstream of G protein-coupled receptors. In this study, we set out to determine the role of Gsα signaling in cells of the early osteoblast lineage in vivo by conditionally deleting Gsα from osterix-expressing cells. This led to severe osteoporosis with fractures at birth, a phenotype that was found to be the consequence of impaired bone formation rather than increased resorption. Osteoblast number was markedly decreased and osteogenic differentiation was accelerated, resulting in the formation of woven bone. Rapid differentiation of mature osteoblasts into matrix-embedded osteocytes likely contributed to depletion of the osteoblast pool. In addition, the number of committed osteoblast progenitors was diminished in both bone marrow stromal cells (BMSCs) and calvarial cells of mutant mice. In the absence of Gsα, expression of sclerostin and dickkopf1 (Dkk1), inhibitors of canonical Wnt signaling, was markedly increased; this was accompanied by reduced Wnt signaling in the osteoblast lineage. In summary, we have shown that Gsα regulates bone formation by at least two distinct mechanisms: facilitating the commitment of mesenchymal progenitors to the osteoblast lineage in association with enhanced Wnt signaling; and restraining the differentiation of committed osteoblasts to enable production of bone of optimal mass, quality, and strength.
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http://dx.doi.org/10.1172/JCI46406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163961PMC
September 2011

Cross-talk between NR4A orphan nuclear receptors and β-catenin signaling pathway in osteoblasts.

Arch Biochem Biophys 2011 May 6;509(1):44-51. Epub 2011 Mar 6.

Institute of Biomedicine/Physiology, Biomedicum Helsinki, University of Helsinki, Finland.

The canonical Wnt signaling pathway and its key mediator β-catenin are important regulators of osteoblast function. NR4A orphan nuclear receptors (Nurr1, NGFI-B, and Nor1) are expressed in osteoblasts and have been shown to regulate the expression of osteoblastic genes and osteoblastic differentiation. Recently, interplay between Nurr1 and the canonical Wnt signaling pathway was reported in 293F cells. We have studied the potential interplay between NR4A receptors and β-catenin in osteoblasts. NR4A receptors repressed β-catenin-mediated transactivation when cotransfected in U2-OS cells. In addition, Nurr1 inhibited β-catenin-mediated expression of Axin2 in MC3T3-E1 cells. The repression involved the DNA-binding domain of NR4A receptors. The repression of β-catenin did not result from reduced β-catenin expression or direct protein-protein interaction between β-catenin and NR4A receptors. β-Catenin was capable of inhibiting the transcriptional activity of NR4A receptors in U2-OS cells by a mechanism that involved the ligand-binding domain of NR4A receptors. As the canonical Wnt signaling pathway and β-catenin are crucial for the development and function of osteoblasts, the repressive effect of NR4A receptors on β-catenin is of potential biological and pathophysiological importance.
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http://dx.doi.org/10.1016/j.abb.2011.02.018DOI Listing
May 2011

Transcriptional activity of estrogen-related receptor γ (ERRγ) is stimulated by the phytoestrogen equol.

J Steroid Biochem Mol Biol 2011 Jan 5;123(1-2):46-57. Epub 2010 Nov 5.

Institute of Biomedicine/Physiology, Biomedicum Helsinki, University of Helsinki, Finland.

Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor lacking identified natural ligands. The synthetic estrogen receptor ligands 4-hydroxytamoxifen and diethylstilbestrol have, however, been shown to bind to and abolish the constitutive transcriptional activity of ERRγ. Certain phytoestrogens were recently reported to act as agonists of the related ERRα. We investigated whether phytoestrogens also modulated the transcriptional activity of ERRγ. We analyzed a selection of phytoestrogens for their potential agonistic or antagonistic activity on ERRγ. In transiently transfected PC-3 and U2-OS cells equol stimulated the transcriptional activity of ERRγ and enhanced its interaction with the coactivator GRIP1. The agonistic effect of equol was abolished by 4-hydroxytamoxifen. Equol induced a conformational change in the ERRγ ligand-binding domain. Based on structural models of the ERRγ ligand-binding domain, we were able to introduce mutations that modulated the agonistic potential of equol. Finally, equol enhanced the growth inhibitory effect of ERRγ on the prostate cancer PC-3 cells. In conclusion, we have demonstrated that the phytoestrogen equol acts as an ERRγ agonist.
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http://dx.doi.org/10.1016/j.jsbmb.2010.11.001DOI Listing
January 2011

ERRalpha regulates osteoblastic and adipogenic differentiation of mouse bone marrow mesenchymal stem cells.

Biochem Biophys Res Commun 2010 May 24;396(2):477-82. Epub 2010 Apr 24.

Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

The orphan nuclear receptor estrogen-related receptor-alpha (ERRalpha) has been reported to have both a positive and a negative regulatory role in osteoblastic and adipocytic differentiation. We have studied the role of ERRalpha in osteoblastic and adipogenic differentiation of mesenchymal stem cells. Bone marrow mesenchymal stem cells were isolated from ERRalpha deficient mice and their differentiation capacities were compared to that of the wild-type cells. ERRalpha deficient cultures displayed reduced cellular proliferation, osteoblastic differentiation, and mineralization. In the complementary experiment, overexpression of ERRalpha in MC3T3-E1 cells increased the expression of osteoblastic markers and mineralization. Alterations in the expression of bone sialoprotein (BSP) may at least partially explain the effects on mineralization as BSP expression was reduced in ERRalpha deficient MSCs and enhanced upon ERRalpha overexpression in MC3T3-E1 cells. Furthermore, a luciferase reporter construct driven by the BSP promoter was efficiently transactivated by ERRalpha. Under adipogenic conditions, ERRalpha deficient cultures displayed reduced adipocytic differentiation. Our data thus propose a positive role for ERRalpha in osteoblastic and adipocytic differentiation. The variability in the results yielded in the different studies implies that ERRalpha may play different roles in bone under different physiological conditions.
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http://dx.doi.org/10.1016/j.bbrc.2010.04.120DOI Listing
May 2010

FGF-8 stimulates the expression of NR4A orphan nuclear receptors in osteoblasts.

Mol Cell Endocrinol 2008 Nov 3;295(1-2):87-93. Epub 2008 Sep 3.

Institute of Biomedicine/Physiology, Biomedicum Helsinki, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland.

Nurr1, NGFI-B, and Nor1 form the NR4A subfamily of orphan nuclear receptors. The NR4A receptors are immediate early genes that can be rapidly induced in response to a variety of stimuli in many cell types, for example, in osteoblasts. Nurr1 regulates the differentiation of osteoblasts and the expression of several osteoblastic genes. Fibroblast growth factor 8b (FGF-8b) regulates osteoblastic differentiation. We show here that treatment of preosteoblastic MC3T3-E1 cells or mouse bone marrow mesenchymal cells with FGF-8b induces the expression of NR4A receptors rapidly and in a dose-dependent manner. This induction involves mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI-3K), and protein kinase C (PKC) pathways. FGF-8b stimulates the proliferation of MC3T3-E1 cells. This effect is enhanced by overexpression of Nurr1 and NGFI-B whereas it is abolished by a dominant negative Nurr1 variant. In conclusion, FGF-8b induces the expression of NR4A orphan nuclear receptors that are involved in mediating the growth promoting effect of FGF-8b in osteoblasts.
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http://dx.doi.org/10.1016/j.mce.2008.08.023DOI Listing
November 2008

Corepressor interaction differentiates the permissive and non-permissive retinoid X receptor heterodimers.

Arch Biochem Biophys 2008 Apr 8;472(2):105-14. Epub 2008 Feb 8.

Institute of Biomedicine/Physiology, Biomedicum Helsinki, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland.

Nurr1 is an orphan nuclear receptor regulating transcription both as a monomer and as a heterodimer with retinoid X receptor (RXR). RXR-Nurr1 heterodimers are permissive RXR heterodimers as they activate transcription in response to RXR ligands. In contrast, heterodimers formed by RXR and retinoic acid receptor (RAR) are non-permissive as they activate transcription only upon RAR ligand binding. We studied the mechanism mediating permissiveness and non-permissiveness by creating receptor chimeras between Nurr1 and RAR. We show that the amino-terminal part of the Nurr1 ligand binding domain conveys permissiveness to RXR-Nurr1 heterodimers. This region is involved in interactions with the corepressors SMRT and NcoR. The corepressors were released from RXR-Nurr1 heterodimers by RXR ligand binding. In contrast, RXR ligand increased the interaction between RXR-RAR heterodimers and the corepressors. The corepressors were released only upon binding of RAR ligand. In conclusion, corepressor interaction differentiates the permissive RXR-Nurr1 heterodimers from the non-permissive RXR-RAR heterodimers.
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http://dx.doi.org/10.1016/j.abb.2008.02.003DOI Listing
April 2008

Cross-talk between the NR3B and NR4A families of orphan nuclear receptors.

Biochem Biophys Res Commun 2007 Jul 25;359(2):391-7. Epub 2007 May 25.

Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

Estrogen-related receptors (NR3B family) and Nurr1, NGFI-B, and Nor1 (NR4A family) are orphan nuclear receptors lacking identified natural ligands. The mechanisms regulating their transcriptional activities have remained elusive. We have previously observed that the members of NR3B and NR4A families are coexpressed in certain cell types such as osteoblasts and that the ability of Nurr1 to transactivate the osteopontin promoter is repressed by ERRs. We have now studied the cross-talk between NR3B and NR4A receptors. We show that NR3B and NR4A receptors mutually repress each others' transcriptional activity. The repression involves intact DNA-binding domains and dimerization interfaces but does not result from competition for DNA binding or from heterodimerization. The activation functions of NR3B and NR4A receptors are dispensable for the cross-talk. In conclusion, we report that cross-talk between NR3B and NR4A receptors is a mechanism modulating the transcriptional activities of these orphan nuclear receptors.
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http://dx.doi.org/10.1016/j.bbrc.2007.05.122DOI Listing
July 2007

Requirements for transcriptional regulation by the orphan nuclear receptor ERRgamma.

Mol Cell Endocrinol 2004 Apr;219(1-2):151-60

Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland.

Estrogen-related receptor gamma (ERRgamma) is an orphan nuclear receptor lacking identified natural ligands. We have addressed the requirements for ERRgamma-mediated gene regulation. ERRgamma transactivates constitutively reporter genes driven by ERR response elements (ERREs) or estrogen response elements (EREs). The activation depends on an intact DNA-binding domain (DBD) and activation function-2 (AF2). ERRgamma-mediated transactivation is further enhanced by peroxisome proliferator-activated receptor coactivator-1. Interestingly, ligand-binding domain (LBD) mutations predicted to either enlarge or diminish the putative ligand-binding pocket have no effect on the transcriptional activity implying that ERRgamma activity does not depend on any ligands. Antiestrogens 4OH-tamoxifen (4OHT) and 4-hydroxytoremifene (4OHtor) inhibit the ability of ERR to transactivate ERRE and ERE reporters. In contrast, ERRgamma activates transcription at AP-1 sites in the presence of 4OHT and 4OHtor. Thus, the transcriptional activity of ERRgamma seems not to require ligand binding but is modulated by binding of certain small synthetic ligands.
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http://dx.doi.org/10.1016/j.mce.2004.01.002DOI Listing
April 2004

Regulation of the osteopontin gene by the orphan nuclear receptor NURR1 in osteoblasts.

Mol Endocrinol 2004 Jun 26;18(6):1546-57. Epub 2004 Feb 26.

Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.

The orphan nuclear receptor Nurr1 is mainly expressed in the central nervous system but is also detected in certain peripheral tissues such as bone. To elucidate the role of Nurr1 in bone, we examined the ability of Nurr1 to regulate osteopontin (OPN) expression in osteoblastic cell lines. Transfection of Nurr1 in osteoblastic cells increased OPN mRNA expression. A dominant negative Nurr1 variant abolished the ability of PTH to induce OPN expression, suggesting that Nurr1 is involved in mediating the regulation of OPN by PTH. Nurr1 efficiently transactivated a luciferase reporter construct driven by the -857/+191 fragment of the mouse OPN promoter. The activation of the OPN promoter was mediated by the monomeric form of Nurr1, required direct binding of Nurr1 to the OPN promoter, and was dependent on the amino-terminal transactivation function-1. The OPN promoter is also regulated by vitamin D receptor and estrogen-related receptors. We show that Nurr1 and vitamin D activate the OPN promoter in a synergistic fashion, whereas Nurr1-mediated transactivation of the OPN promoter is repressed by estrogen-related receptors. In conclusion, Nurr1 activates the OPN promoter directly in osteoblastic cells, suggesting a role for Nurr1 in the regulation of bone homeostasis.
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http://dx.doi.org/10.1210/me.2003-0247DOI Listing
June 2004

Dimerization modulates the activity of the orphan nuclear receptor ERRgamma.

Biochem Biophys Res Commun 2004 Feb;314(4):964-70

Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, Finland.

Estrogen-related receptor gamma (ERRgamma) is an orphan nuclear receptor lacking identified natural ligands. However, 4-hydroxytamoxifen and diethylstilbestrol were recently shown to bind to and inhibit ERRgamma activity. ERR activates transcription constitutively as a monomer. We show here that ERRgamma forms also dimers via its ligand-binding domain. Homodimerization enhances the transcriptional activity. In contrast, heterodimerization with the related receptor ERRalpha inhibits the activities of both ERRgamma and ERRalpha. The inverse ERRgamma agonist 4OHT further inhibits the activity of the ERRgamma-ERRalpha heterodimer, indicating that 4OHT may modulate ERRalpha signaling via ERRgamma. Receptor dimerization thus modulates the transcriptional activities of ERRs.
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http://dx.doi.org/10.1016/j.bbrc.2003.12.194DOI Listing
February 2004

Defining an N-terminal activation domain of the orphan nuclear receptor Nurr1.

Biochem Biophys Res Commun 2004 Jan;313(1):205-11

Ludwig Institute for Cancer Research, Stockholm Branch, Box 240, Stockholm S-171 77, Sweden.

Nurr1 is an orphan nuclear receptor essential for the development of midbrain dopaminergic neurons. Activation of Nurr1 depends on two so-called activation functions (AFs) situated in the N- and C-terminal regions, respectively. The region important for activation within the C-terminal domain has been shown to promote activation in a highly cell-type specific fashion in the absence of added exogenous ligands. In contrast, the region in the N-terminal domain (AF1) has been much less characterized. Here we mutagenized the N-terminal domain of Nurr1 to define essential activation regions. The results identified a short core activation region localized close to the N-terminus of Nurr1. In addition, cell-type specific influences by other signaling pathways were analyzed by mutagenesis of specific conserved phosphorylation sites. The results indicate that mitogen-activated protein kinase activity (MAPK) positively influences Nurr1 AF1-dependent transcriptional activation via a conserved phosphorylation site outside the core activation region.
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http://dx.doi.org/10.1016/j.bbrc.2003.11.079DOI Listing
January 2004

Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells.

Exp Cell Res 2003 Aug;288(2):324-34

Ludwig Institute for Cancer Research, Stockholm Branch, P.O. Box 240, S-171 77 Stockholm, Sweden.

Nurr1, a transcription factor belonging to the nuclear receptor family, is essential for the generation of midbrain dopamine (DA) cells during embryonic development. Nurr1 continues to be expressed in adult DA neurons but the role for Nurr1 in inducing and regulating basic dopaminergic functions such as dopamine synthesis and storage has remained unknown. We have previously used MN9D dopamine cells to analyze the role of Nurr1 and retinoids in DA cell maturation. These studies demonstrated that both Nurr1 and retinoids induce cell cycle arrest and a mature morphology. Here we used MN9D cells to investigate how Nurr1 regulates dopaminergic functions. Our results demonstrate that Nurr1, but not retinoids, increases DA content and the expression of aromatic L-amino acid decarboxylase (AADC) and vesicular monoamine transporter-2 (VMAT2) in MN9D cells. In a Nurr1-inducible cell line upregulation of VMAT2 is dependent on continuous Nurr1 expression. Moreover, AADC and VMAT2 are deregulated in midbrain DA cells of Nurr1 knockout embryos as revealed by in situ hybridization. Together, the results provide evidence indicating an instructive role for Nurr1 in controlling DA synthesis and storage.
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http://dx.doi.org/10.1016/s0014-4827(03)00216-7DOI Listing
August 2003

Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors.

Nature 2003 May;423(6939):555-60

Department of Structural Biology, Tularik Inc., 1120 Veterans Blvd., South San Francisco, California 94080, USA.

Members of the nuclear receptor (NR) superfamily of transcription factors modulate gene transcription in response to small lipophilic molecules. Transcriptional activity is regulated by ligands binding to the carboxy-terminal ligand-binding domains (LBDs) of cognate NRs. A subgroup of NRs referred to as 'orphan receptors' lack identified ligands, however, raising issues about the function of their LBDs. Here we report the crystal structure of the LBD of the orphan receptor Nurr1 at 2.2 A resolution. The Nurr1 LBD adopts a canonical protein fold resembling that of agonist-bound, transcriptionally active LBDs in NRs, but the structure has two distinctive features. First, the Nurr1 LBD contains no cavity as a result of the tight packing of side chains from several bulky hydrophobic residues in the region normally occupied by ligands. Second, Nurr1 lacks a 'classical' binding site for coactivators. Despite these differences, the Nurr1 LBD can be regulated in mammalian cells. Notably, transcriptional activity is correlated with the Nurr1 LBD adopting a more stable conformation. Our findings highlight a unique structural class of NRs and define a model for ligand-independent NR function.
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http://dx.doi.org/10.1038/nature01645DOI Listing
May 2003

Defining requirements for heterodimerization between the retinoid X receptor and the orphan nuclear receptor Nurr1.

J Biol Chem 2002 Sep 18;277(38):35118-23. Epub 2002 Jul 18.

Ludwig Institute for Cancer Research, Karolinska Institute, Stockholm, Sweden SE 171 77.

Nurr1, an orphan nuclear receptor mainly expressed in the central nervous system, is essential for the development of the midbrain dopaminergic neurons. Nurr1 binds DNA as a monomer and exhibits constitutive transcriptional activity. Nurr1 can also regulate transcription as a heterodimer with the retinoid X receptor (RXR) and activate transcription in response to RXR ligands. However, the specific physiological roles of Nurr1 monomers and RXR-Nurr1 heterodimers remain to be elucidated. The aim of this study was to define structural requirements for RXR-Nurr1 heterodimerization. Several amino acid substitutions were introduced in both Nurr1 and RXR in the I-box, a region previously shown to be important for nuclear receptor dimerization. Single amino acid substitutions introduced in either Nurr1 or RXR abolished heterodimerization. Importantly, heterodimerization-deficient Nurr1 mutants exhibited normal activities as monomers. Thus, by introducing specific amino acid substitutions in Nurr1, monomeric and heterodimeric properties of Nurr1 can be distinguished. Interestingly, substitutions in the RXR I-box differentially affected heterodimerization with Nurr1, retinoic acid receptor, thyroid hormone receptor, and constitutive androstane receptor demonstrating that the dimerization interfaces in these different heterodimers are functionally unique. Furthermore, heterodimerization between RXR and Nurr1 had a profound influence on the constitutive activity of Nurr1, which was diminished as a result of RXR interaction. In conclusion, our data show unique structural and functional properties of RXR-Nurr1 heterodimers and also demonstrate that specific mutations in Nurr1 can abolish heterodimerization without affecting other essential functions.
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http://dx.doi.org/10.1074/jbc.M201707200DOI Listing
September 2002
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