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Hudson Institute of Medical Research, Clayton, Australia
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of a protective role of ACE2 in the early stage of hypertension that is lost at later stages of disease ( Keidar et al. 2005 , 2007 ). Nuclear receptors other than MR, glucocorticoid receptor (GR) and oestrogen receptor (ER) can also regulate ACE2
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Houston Methodist Research Institute, College of Arts and Sciences, Departments of Paediatrics, Children's Health Research Institute, Department of Molecular Physiology and Biophysics, The Third Affiliated Hospital of Guangzhou Medical University, Genomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USA
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Houston Methodist Research Institute, College of Arts and Sciences, Departments of Paediatrics, Children's Health Research Institute, Department of Molecular Physiology and Biophysics, The Third Affiliated Hospital of Guangzhou Medical University, Genomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USA
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Thyroid hormone (TH) acts through specific receptors (TRs), which are conditional transcription factors, to induce fibroblast growth factor 21 (FGF21), a peptide hormone that is usually induced by fasting and that influences lipid and carbohydrate metabolism via local hepatic and systemic endocrine effects. While TH and FGF21 display overlapping actions when administered, including reductions in serum lipids, according to the current models these hormones act independently in vivo. In this study, we examined mechanisms of regulation of FGF21 expression by TH and tested the possibility that FGF21 is required for induction of hepatic TH-responsive genes. We confirm that active TH (triiodothyronine (T3)) and the TRβ-selective thyromimetic GC1 increase FGF21 transcript and peptide levels in mouse liver and that this effect requires TRβ. T3 also induces FGF21 in cultured hepatocytes and this effect involves direct actions of TRβ1, which binds a TRE within intron 2 of FGF21. Gene expression profiles of WT and Fgf21-knockout mice are very similar, indicating that FGF21 is dispensable for the majority of hepatic T3 gene responses. A small subset of genes displays diminished T3 response in the absence of FGF21. However, most of these are not obviously directly involved in T3-dependent hepatic metabolic processes. Consistent with these results, T3-dependent effects on serum cholesterol are maintained in the Fgf21 −/− background and we observe no effect of the Fgf21-knockout background on serum triglycerides and glucose. Our findings indicate that T3 regulates the genes involved in classical hepatic metabolic responses independently of FGF21.
Section of Hematology and Medical Oncology, Structural and Cellular Biology, Department of Medical Genetics, Center for Nuclear Receptors and Cell Signaling, Department of Medicine, Tulane University, 1430 Tulane Avenue, SL-78, New Orleans, Louisiana 70112, USA Departments of
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Section of Hematology and Medical Oncology, Structural and Cellular Biology, Department of Medical Genetics, Center for Nuclear Receptors and Cell Signaling, Department of Medicine, Tulane University, 1430 Tulane Avenue, SL-78, New Orleans, Louisiana 70112, USA Departments of
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The estrogen receptor α (ERα) is a transcription factor that mediates the biological effects of 17β-estradiol (E2). ERα transcriptional activity is also regulated by cytoplasmic signaling cascades. Here, several Gα protein subunits were tested for their ability to regulate ERα activity. Reporter assays revealed that overexpression of a constitutively active Gαo protein subunit potentiated ERα activity in the absence and presence of E2. Transient transfection of the human breast cancer cell line MCF-7 showed that Gαo augments the transcription of several ERα-regulated genes. Western blots of HEK293T cells transfected with ER±Gαo revealed that Gαo stimulated phosphorylation of ERK 1/2 and subsequently increased the phosphorylation of ERα on serine 118. In summary, our results show that Gαo, through activation of the MAPK pathway, plays a role in the regulation of ERα activity.
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Vitamin D plays a major role in bone mineral homeostasis by promoting the transport of calcium and phosphate to ensure that the blood levels of these ions are sufficient for the normal mineralization of type I collagen matrix in the skeleton. In contrast to classic vitamin D-deficiency rickets, a number of vitamin D-resistant rachitic syndromes are caused by acquired and hereditary defects in the metabolic activation of the vitamin to its hormonal form, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), or in the subsequent functions of the hormone in target cells. The actions of 1,25(OH)2D3 are mediated by the nuclear vitamin D receptor (VDR), a phosphoprotein which binds the hormone with high affinity and regulates the expression of genes via zinc finger-mediated DNA binding and protein–protein interactions. In hereditary hypocalcemic vitamin D-resistant rickets (HVDRR), natural mutations in human VDR that confer patients with tissue insensitivity to 1,25(OH)2D3 are particularly instructive in revealing VDR structure/function relationships. These mutations fall into three categories: (i) DNA binding/nuclear localization, (ii) hormone binding and (iii) heterodimerization with retinoid X receptors (RXRs). That all three classes of VDR mutations generate the HVDRR phenotype is consistent with a basic model of the active receptor as a DNA-bound, 1,25(OH)2D3-liganded heterodimer of VDR and RXR. Vitamin D responsive elements (VDREs) consisting of direct hexanucleotide repeats with a spacer of three nucleotides have been identified in the promoter regions of positively controlled genes expressed in bone, such as osteocalcin, osteopontin, β3-integrin and vitamin D 24-OHase. The 1,25(OH)2D3 ligand promotes VDR-RXR heterodimerization and specific, high affinity VDRE binding, whereas the ligand for RXR, 9-cis retinoic acid (9-cis RA), is capable of suppressing 1,25(OH)2D3-stimulated transcription by diverting RXR to form homodimers. However, initial 1,25(OH)2D3 liganding of a VDR monomer renders it competent not only to recruit RXR into a heterodimer but also to conformationally silence the ability of its RXR partner to bind 9-cis RA and dissociate the heterodimer. Additional probing of protein–protein interactions has revealed that VDR also binds to basal transcription factor IIB (TFIIB) and, in the presence of 1,25(OH)2D3, an RXR-VDR-TFIIB ternary complex can be created in solution. Moreover, for transcriptional activation by 1,25(OH)2D3, both VDR and RXR require an intact short amphipathic α-helix, known as AF-2, positioned at their extreme C-termini. Because the AF-2 domains participate neither in VDR-RXR heterodimerization nor in TFIIB association, it is hypothesized that they contact, in a ligand-dependent fashion, transcriptional coactivators such as those of the steroid receptor coactivator family, constituting yet a third protein–protein interaction for VDR. Therefore, in VDR-mediated transcriptional activation, 1,25(OH)2D3 binding to VDR alters the conformation of the ligand binding domain such that it: (i) engages in strong heterodimerization with RXR to facilitate VDRE binding, (ii) influences the RXR ligand binding domain such that it is resistant to the binding of 9-cis RA but active in recruiting coactivator to its AF-2 and (iii) presents the AF-2 region in VDR for coactivator association. The above events, including bridging by coactivators to the TATA binding protein and associated factors, may position VDR such that it is able to attract TFIIB and the balance of the RNA polymerase II transcription machinery, culminating in repeated transcriptional initiation of VDRE-containing, vitamin D target genes. Such a model would explain the action of 1,25(OH)2D3 to elicit bone remodeling by stimulating osteoblast and osteoclast precursor gene expression, while concomitantly triggering the termination of its hormonal signal by inducing the 24-OHase catabolizing enzyme.
Journal of Endocrinology (1997) 154, S57–S73
Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
Department of General Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
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Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia
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Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
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Royal College of Surgeons in Ireland, Dublin, Ireland
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Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
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Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
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Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
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MR activation in macrophages is critical for the development of cardiac inflammation and fibrosis. We previously showed that MR activation modifies macrophage pro-inflammatory signalling, changing the cardiac tissue response to injury via both direct gene transcription and JNK/AP-1 second messenger pathways. In contrast, MR-mediated renal electrolyte homeostasis is critically determined by DNA-binding-dependent processes. Hence, ascertaining the relative contribution of MR actions via DNA binding or alternative pathways on macrophage behaviour and cardiac inflammation may provide therapeutic opportunities which separate the cardioprotective effects of MR antagonists from their undesirable renal potassium-conserving effects. We developed new macrophage cell lines either lacking MR or harbouring a mutant MR incapable of DNA binding. Western blot analysis demonstrated that MR DNA binding is required for lipopolysaccharide (LPS), but not phorbol 12-myristate-13-acetate (PMA), induction of the MAPK/pJNK pathway in macrophages. Quantitative RTPCR for pro-inflammatory and pro-fibrotic targets revealed subsets of LPS- and PMA-induced genes that were either enhanced or repressed by the MR via actions that do not always require direct MR-DNA binding. Analysis of the MR target gene and profibrotic factor MMP12 identified promoter elements that are regulated by combined MR/MAPK/JNK signalling. Evaluation of cardiac tissue responses to an 8-day DOC/salt challenge in mice selectively lacking MR DNA-binding in macrophages demonstrated levels of inflammatory markers equivalent to WT, indicating non-DNA binding-dependent MR signalling in macrophages is sufficient for DOC/salt-induced tissue inflammation. Our data demonstrate that the MR regulates a macrophage pro-inflammatory phenotype and cardiac tissue inflammation, partially via pathways that do not require DNA binding.
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Estrogen treatment has positive effects on the skeleton, and we have shown that estrogen receptor alpha (ERα) expression in cells of hematopoietic origin contributes to a normal estrogen treatment response in bone tissue. T lymphocytes are implicated in the estrogenic regulation of bone mass, but it is not known whether T lymphocytes are direct estrogen target cells. Therefore, the aim of this study was to determine the importance of ERα expression in T lymphocytes for the estrogenic regulation of the skeleton using female mice lacking ERα expression specifically in T lymphocytes (Lck-ERα−/−) and ERαflox/flox littermate (control) mice. Deletion of ERα expression in T lymphocytes did not affect bone mineral density (BMD) in sham-operated Lck-ERα−/− compared to control mice, and ovariectomy (ovx) resulted in a similar decrease in BMD in control and Lck-ERα−/− mice compared to sham-operated mice. Furthermore, estrogen treatment of ovx Lck-ERα−/− led to an increased BMD that was indistinguishable from the increase seen after estrogen treatment of ovx control mice. Detailed analysis of both the appendicular (femur) and axial (vertebrae) skeleton showed that both trabecular and cortical bone parameters responded to a similar extent regardless of the presence of ERα in T lymphocytes. In conclusion, ERα expression in T lymphocytes is dispensable for normal estrogenic regulation of bone mass in female mice.
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HL60 cells differentiate to monocytes or neutrophils in response to 1 alpha,25(OH)2-vitamin D3 (D3) and retinoids respectively. D3 and retinoid actions converge since their receptors (VDR, RAR) heterodimerise with a common partner, RXR, which also interacts with thyroid hormone (T3) receptors (T3R). HL60 cells were treated with combinations of D3 and retinoids to induce differentiation and to investigate whether increased VDR or RAR expression correlated with monocyte or neutrophil differentiation and whether altered receptor concentrations affected DNA-binding specificity. As assessed by Western blotting, VDR and RXR expression was unchanged in monocytes relative to controls but levels of RAR and T3R were reduced. In contrast, only VDR expression was reduced in neutrophils. T3 did not promote differentiation or influence its induction by D3 or retinoids and did not affect expression of any receptor. Gel mobility-shift analysis revealed that nuclear extracts from undifferentiated cells, monocytes and neutrophils interacted differently with VDRE-, RARE- and RXRE-binding sites. Monocyte nuclear protein/DNA complexes contain readily detectable VDR and RXR whereas neutrophil complexes contain RAR and RXR. Thus hormone-induced changes in receptor stoichiometry favour either VDR/RXR or RAR/RXR heterodimerisation and correlate with hormone-induced differentiation of HL60 cells to monocytes or neutrophils respectively.
Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Korea
Laboratory of Reproductive Biology and Infertility, Cheil General Hospital, Women’s Healthcare Center, Seoul 100-380, Korea
Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07101-1709, USA
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Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Korea
Laboratory of Reproductive Biology and Infertility, Cheil General Hospital, Women’s Healthcare Center, Seoul 100-380, Korea
Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07101-1709, USA
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Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Korea
Laboratory of Reproductive Biology and Infertility, Cheil General Hospital, Women’s Healthcare Center, Seoul 100-380, Korea
Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07101-1709, USA
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Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Korea
Laboratory of Reproductive Biology and Infertility, Cheil General Hospital, Women’s Healthcare Center, Seoul 100-380, Korea
Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07101-1709, USA
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Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Korea
Laboratory of Reproductive Biology and Infertility, Cheil General Hospital, Women’s Healthcare Center, Seoul 100-380, Korea
Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07101-1709, USA
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Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Korea
Laboratory of Reproductive Biology and Infertility, Cheil General Hospital, Women’s Healthcare Center, Seoul 100-380, Korea
Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07101-1709, USA
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Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Korea
Laboratory of Reproductive Biology and Infertility, Cheil General Hospital, Women’s Healthcare Center, Seoul 100-380, Korea
Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07101-1709, USA
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Introduction Retinoids, e.g. retinoic acids (RA), utilize two subfamilies of nuclear receptors, retinoic acid receptors (RARs), and retinoid X receptors (RXRs). Three subtypes of RAR, α, β, and γ, exist as receptors of trans - and 9
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ABSTRACT
The time-course of changes in the nuclear 3,5,3′-tri-iodothyronine (T3) receptor-binding capacity (Bmax) of longissimus dorsi muscle has been investigated in cold-acclimated young pigs after a single large meal. Measurement of Bmax values 4, 8, 12 and 24 h after feeding indicated a decline in receptor numbers after food intake with the lowest values occurring at 8 h. The receptor numbers then increased significantly, with the values at 12 h being more than 50% higher than those obtained at 8 h. The Bmax values reached their highest level 24 h after feeding. No significant changes in the dissociation constant were observed. Possible reasons for the changes in T3 receptor numbers are discussed and it is suggested that the increase in T3 receptor numbers 12–24 h after feeding may play a role in enhancing the thermogenic capacity of the tissues in response to food.
Journal of Endocrinology (1992) 134, 67–72
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