Widely spaced, directly repeated PuGGTCA elements act as promiscuous enhancers for different classes of nuclear receptors.

We describe here a novel class of cis-acting response elements for retinoid, vitamin D, and estrogen receptors which are widely spaced (10 to 200 bp) direct repeats (DRs) of the canonical 5'-AGGTCA half-site recognition motif (DR10 to DR200). In contrast to the specificity previously observed with shortly spaced DRs (DR1 to DR5), the different receptors bind promiscuously to these novel elements to activate transcription in the presence of retinoic acid (RA), vitamin D, or estrogen. The greatest RA-dependent transactivation, seen with DR15, was similar to that observed with the canonical DR5. Both RA receptors and retinoid X receptors contribute to transactivation through widely spaced DR elements. With the estrogen receptor, DR15 was one-third as efficient as the classical palindromic response element. A further increase of spacer lengths progressively decreased the efficiency of transactivation. No transactivation was seen with widely spaced DRs when the thyroid and retinoid X receptors were coexpressed in the presence of their ligands. The progesterone receptor was also unable to transactivate through a DR10 element composed of its cognate binding motifs. These results considerably extend the response element repertoire of nuclear receptors and suggest the existence of promiscuous transcriptional regulation through common response elements, as well as the possibility of receptor "cross-talk."

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Multiple parameters control the selectivity of nuclear receptors for their response elements. Selectivity and promiscuity in response element recognition by retinoic acid receptors and retinoid X receptors.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)54192-2 ◽

1993 ◽

Vol 268 (1) ◽

pp. 591-600

Author(s):

S. Mader ◽

P. Leroy ◽

J.Y. Chen ◽

P. Chambon

Keyword(s):

Retinoic Acid ◽

Nuclear Receptors ◽

Retinoic Acid Receptors ◽

Response Element ◽

Retinoid X Receptors ◽

Response Elements ◽

Multiple Parameters ◽

X Receptors

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Response element selectivity for heterodimerization of vitamin D receptors with retinoic acid and retinoid X receptors

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0120327 ◽

1994 ◽

Vol 12 (3) ◽

pp. 327-339 ◽

Cited By ~ 44

Author(s):

M Schräder ◽

K M Müller ◽

M Becker-André ◽

C Carlberg

Keyword(s):

Vitamin D ◽

Retinoic Acid ◽

Specific Response ◽

Direct Repeats ◽

Response Element ◽

Retinoid X Receptors ◽

Response Elements ◽

Vitamin D Receptors ◽

Receptor Complexes ◽

X Receptors

ABSTRACT The transcription of vitamin D (VD) responsive genes is regulated by three different nuclear signalling pathways mediated by homodimers of VD receptors (VDRs), heterodimers of VDRs and retinoid X receptors (RXRs) and heterodimers of VDRs with retinoic acid receptors (RARs). Here, the in vitro DNA-binding affinity of all three receptor complexes was shown to be enhanced by the presence of VD. However, the specificity of the three pathways was dictated by the differential affinities of the receptor complexes for VD response elements. Potential response elements were distinguished by the sequence, the separation and the relative orientation of the hexameric core binding motifs. It was found that both VDR-RAR and VDR-RXR heterodimers act functionally on all three response element configurations: direct repeats, palindromes and inverted palindromes. With direct repeats, neither heterodimer type showed a preference for any of the three principal core motifs, (A/G)GGTGA, (A/G)GGTCA and (A/G)GTTCA. However, while they did exhibit preferences for core motifs in palindromes, the spacing requirements were identical for both complexes. Inverted palindromes, however, formed the most specific response elements. A simple model explains a steric link between the optimal spacing of direct repeats and that of inverted palindromes. Taken together, the experimental data and the model provide further criteria for the screening of VD responsive genes.

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Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching.

Molecular and Cellular Biology ◽

10.1128/mcb.13.12.7698 ◽

1993 ◽

Vol 13 (12) ◽

pp. 7698-7707 ◽

Cited By ~ 66

Author(s):

J M Lehmann ◽

X K Zhang ◽

G Graupner ◽

M O Lee ◽

T Hermann ◽

...

Keyword(s):

Thyroid Hormone ◽

Nuclear Receptors ◽

Cross Talk ◽

Transcriptional Activation ◽

Hormone Receptors ◽

Retinoid X Receptor ◽

Thyroid Hormone Receptors ◽

Retinoid X Receptors ◽

Response Elements ◽

X Receptors

Thyroid hormone receptors (TRs) form heterodimers with retinoid X receptors (RXRs). Heterodimerization is required for efficient TR DNA binding to most response elements and transcriptional activation by thyroid hormone. RXRs also function as auxiliary proteins for several other receptors. In addition, RXR alpha can be induced by specific ligands to form homodimers. Here we report that RXR-specific retinoids that induce RXR homodimers are effective repressors of the T3 response. We provide evidence that this repression by RXR-specific ligands occurs by sequestering of RXR from TR-RXR heterodimers into RXR homodimers. This ligand-induced squelching may represent an important mechanism by which RXR-specific retinoids and 9-cis retinoic acid mediate hormonal cross talk among a subfamily of nuclear receptors activated by structurally unrelated ligands.

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Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching

Molecular and Cellular Biology ◽

10.1128/mcb.13.12.7698-7707.1993 ◽

1993 ◽

Vol 13 (12) ◽

pp. 7698-7707

Author(s):

J M Lehmann ◽

X K Zhang ◽

G Graupner ◽

M O Lee ◽

T Hermann ◽

...

Keyword(s):

Thyroid Hormone ◽

Nuclear Receptors ◽

Cross Talk ◽

Transcriptional Activation ◽

Hormone Receptors ◽

Retinoid X Receptor ◽

Thyroid Hormone Receptors ◽

Retinoid X Receptors ◽

Response Elements ◽

X Receptors

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Cloning and activity analysis of the promoter of nucleotide exchange factor gene ZjFes1 from the seagrasses Zostera japonica

Scientific Reports ◽

10.1038/s41598-020-74381-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Siting Chen ◽

Guanglong Qiu

Keyword(s):

Regulatory Element ◽

Light Response ◽

Zostera Japonica ◽

Nucleotide Exchange ◽

Root Tips ◽

Response Element ◽

Response Elements ◽

Cis Acting ◽

Exchange Factor ◽

Nucleotide Exchange Factor

Abstract After HSP70 binds to the J domain of the substrate and co-chaperone protein, ATP is hydrolyzed to ADP, and the nucleotide exchange factors (NEFs) promote the release of ADP. Under physiological conditions, the nucleotide exchange step is the rate-limiting step, which is accelerated by NEFs. In this study, the promoter of nucleotide exchange factor ZjFes1 was cloned, and its expression in tissues and under heat stress was studied to understand the regulatory mechanism of ZjFes1 and provide the molecular basis to study heat tolerance mechanism of seagrass. It was found that the promoter has common cis-acting elements in promoter and enhancer regions CAAT-box, as well as light response elements AE-box, Box 4 and TCCC-motif, a cis-acting regulatory element essential for the anaerobic induction of ARE, hormone response elements CGTCA-motif and TGACG-motif (MeJA response element), GARE-motif (gibberellin response element), TGA-element (auxin response element), a cis-acting regulatory element related to meristem expression CAT-box, and a cis-acting element involved in defense and stress responsiveness of TC-rich repeats. Two-week-old seedlings exhibited weak GUS activities in their cotyledons. In addition, the AtFes1A promoter was constitutively active in the anthers. After exposure to 38 °C for 2 h, the root tips of two-week-old seedlings were stained a strong blue. Heat-inducible activities of GUS were also observed in the cotyledons, roots, leaves, anthers, sepals and siliques.

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The function of retinoid X receptors on negative thyroid hormone response elements

Molecular and Cellular Endocrinology ◽

10.1016/s0303-7207(97)04025-2 ◽

1997 ◽

Vol 128 (1-2) ◽

pp. 85-96 ◽

Cited By ~ 8

Author(s):

Teiji Takeda ◽

Takeshi Nagasawa ◽

Takahide Miyamoto ◽

Kiyoshi Hashizume ◽

Leslie J DeGroot

Keyword(s):

Thyroid Hormone ◽

Hormone Response ◽

Retinoid X Receptors ◽

Response Elements ◽

Hormone Response Elements ◽

X Receptors

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Nuclear Receptors Are Differentially Expressed and Activated in KAIMRC1 Compared to MCF7 and MDA-MB231 Breast Cancer Cells

Molecules ◽

10.3390/molecules24112028 ◽

2019 ◽

Vol 24 (11) ◽

pp. 2028

Author(s):

Atef Nehdi ◽

Rizwan Ali ◽

Alshaimaa Alhallaj ◽

Hajar Alzahrani ◽

Nosaibah Samman ◽

...

Keyword(s):

Vitamin D ◽

Retinoic Acid ◽

Cell Lines ◽

Nuclear Receptors ◽

Vitamin D Receptor ◽

Luciferase Reporter ◽

Peroxisome Proliferator ◽

Response Element ◽

Receptor Alpha ◽

Receptor Response

We recently established a KAIMRC1 cell line that has unique features compared to the known breast cancer cell lines, MCF7 and MDA-MB231. To characterize it further, we investigated the expression profile of nuclear receptors and their respective co-factors in these cell lines. We confirm that in contrast to the triple negative cell line MDA-MB231, the MCF7 and KAIMRC1 are estrogen receptor alpha (ERa) and progesterone receptor alpha (PRa) positive, with significant lower expression of these receptors in KAIMRC1. KAIMRC1 cell is a vitamin D receptor (VDR) negative and V-ErbA-Related Protein 2 (EAR2) positive in contrast to MCF7 and MDA-MB231. Remarkably, the histone deacetylases (HDACs) are highly expressed in KAIRMC1 with HDAC6 and HDAC 7 are exclusively expressed in KAIMRC1 while thyroid hormone receptor-associated protein 80 (TRAP80), telomeric DNA binding protein 1 (TBP1) and TGF-beta receptor interacting protein (TRIP1) are absent in KAIMRC1 but present in MCF7 and MDA-MB231. In a luciferase reporter assay, the ERa coexpression is needed for estrogen receptor element (ERE)-luciferase activation by estradiol in KAIMRC1 but not in MCF7. The co-expression of exogenous Liver X receptor alpha (LXRa)/retinoid X receptor alpha (RXRa) are necessary for LXR responsive element (LXRE) activation by the GW3696 in the three cell lines. However, the activity of peroxisome proliferator-activated receptor response element (PPARE)-tk-luciferase reporter increased when peroxisome proliferator-activated receptors alpha (PPARa)/RXRa were coexpressed but the addition of PPARa agonist (GW7647) did not stimulate further the reporter. The signal of the PPARE reporter increased in a dose-dependent manner with rosiglitazone (PPARg agonist) in KAIMRC1, MCF7, and MDA-MB231 when the proliferator-activated receptors gamma (PPARg)/RXRa receptors were cotransfected. Retinoic acid-induced activation of retinoic acid receptor response element (RARE)-tk-luciferase is dependent on exogenous expression of retinoic acid receptor alpha (RARa)/RXRa heterodimer in MDA-MB 231 but not in MCF7 and KAIMRC1 cell lines. In the three cell lines, Bexarotene-induced retinoid X receptor response element (RXRE)-luciferase reporter activation was induced only if the RXRa/LXRa heterodimer were co-expressed. The vitamin D receptor response element (VDRE)-luciferase reporter activity showed another distinct feature of KAIMRC1, where only co-expression of exogenous vitamin D receptor (VDR)/RXRa heterodimer was sufficient to reach the maximum rate of activation of VDRE reporter. In the proliferation assay, nuclear receptors ligands showed a distinct effect on KAIMRC1 compared to MCF7 and MDA-MB231. Growth inhibition effects of used ligands suggest that KAIMRC1 correlate more closely to MDA-MB231 than MCF7. Vitamin D3, rosiglitazone, novel RXR compound (RXRc) and PPARa compound (GW6471) have the most profound effects. In conclusion, we showed that nuclear receptors are differentially expressed, activated and also their ligand produced distinct effects in KAIMRC1 compared to MCF7 and MDA-MB231. This finding gives us confidence that KAIMRC1 has a unique biological phenotype.

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