Comparison of 6-s-cis- and 6-s-trans-Locked Analogs of 1α,25-Dihydroxyvitamin D3 Indicates That the 6-s-cis Conformation Is Preferred for Rapid Nongenomic Biological Responses and That Neither 6-s-cis- nor 6-s-trans-Locked Analogs Are Preferred for Genomic Biological Responses

Norman, Anthony W.; Okamura, William H.; Hammond, Marion W.; Bishop, June E.; Dormanen, Murray C.; Bouillon, Roger; Baelen, Hugo Van; Ridall, Amy L.; Daane, E.; Khoury, Ramzi; Farach‐Carson, Mary C.

doi:10.1210/mend.11.10.9993

Cited by 41 publications

(29 citation statements)

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“…Whereas the 6-s-cis-locked JN (Fig. 1 A) is a full agonist for 1,25D-mediated rapid responses, it is only a weak genomic agonist (10). These results parallel the structural and molecular evidence that 1,25D genomic responses are mediated by its 6-s-trans form.…”

Section: Identification Of An a Pocket In The Vdr Lbd: A-ring And Sidsupporting

confidence: 64%

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Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH) ₂ -vitamin D ₃ signaling

Mizwicki

Keidel

Bula

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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T he steroid hormone 1␣,25(OH) 2 -vitamin D 3 (1,25D) (Fig. 1A), other steroid hormones, retinoids, and thyroid hormones form the family of ligands for the nuclear receptor (NR) superfamily (1), the members of which produce genomic responses through selective interaction of the liganded receptor with promoters of appropriate genes and basal transcription machinery. Many of these hormones also activate rapid, nongenomic (NG), cellular signaling cascades (2, 3) (except retinoids) that range from activation of ion channels (4, 5) to promoting kinase and other cytosolic signaling cascades (6-9). Defining the structure-function requirements for 1,25D and 17␤-estradiol (E 2 ) rapid actions has been aided by the synthesis of analogs that are NG agonists like 1␣,25(OH) 2 -lumisterol (JN) (ref. 10 and Fig. 1 A) and 4-estren-3␣,17␤-diol (EST) (11) or antagonists like 1␤,25(OH) 2 -vitamin D 3 (HL) (ref. 12 and Fig. 1 A), but that are only weak genomic transactivators (13). Thus, important structural attributes of the sterol dictate its agonistic properties and subsequent genomic vs. NG signaling profile (14, 15).When 1,25D rapid signaling cascades were first discovered, it was hypothesized that the observed activities were propagated by a novel membrane protein(s) (16), because analogs JN and HL did not compete well with [ 3 H]1,25D for binding to the nuclear vitamin D receptor (VDR) (17). Recently, in studies using a VDR knockout (KO) mouse (18) and a naturally occurring human VDR mutation (19), 1,25D-mediated rapid responses were shown to require a functional VDR. Both the VDR and estrogen receptor (ER) have been found localized to the plasma membrane in caveolae (7, 20); therefore, it has been proposed that the VDR and ER propagate some NG signaling (6,9,18,21,22). However, given the poor affinity of JN and HL for the VDR, it is difficult to understand how these sterols can facilitate their activities through the VDR.Results obtained from the modeling (INSIGHT 2000.1) of JN, 1,25D, and HL in the VDR ligand-binding domain (LBD) showed that the VDR could possibly accept and form favorable nonbonding interactions with vitamin D sterols in a distinct ligand-binding pocket [an alternative ligand-binding pocket (A pocket)] from the genomic pocket (G pocket) that was previously defined by x-ray crystallography (23, 24). Our proposed A-pocket accepts ligands that differ in shape from those in the classical G pocket (3,23,24).The data from these models has led to the proposal that the VDR can function as a rapid response receptor through a conformational ensemble mechanism (3, 25) whereby the flexible 1,25D steroid hormone samples an ensemble of energetically similar protein conformations (26). In addition, the ensemble model and existence of an A pocket may provide an explanation for the observed sex-nonspecific, nongenotropic signaling through the ER␣ receptor by EST (3, 9, 11). The physiological relevance of the ensemble model and functional importance of an A pocket within the VDR is further substantiated by applying the m...

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Section: Identification Of An a Pocket In The Vdr Lbd: A-ring And Sidsupporting

confidence: 64%

“…Defining the structure-function requirements for 1,25D and 17␤-estradiol (E 2 ) rapid actions has been aided by the synthesis of analogs that are NG agonists like 1␣,25(OH) 2 -lumisterol (JN) (ref. 10 and Fig. 1 A) and 4-estren-3␣,17␤-diol (EST) (11) or antagonists like 1␤,25(OH) 2 -vitamin D 3 (HL) (ref.…”

mentioning

confidence: 99%

Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH) ₂ -vitamin D ₃ signaling

Mizwicki

Keidel

Bula

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…3B). Both analogs are potent agonists for the rapid membrane-mediated effects of 1␣,25(OH) 2 D 3 but associate poorly with the classical VDR under equilibrium binding conditions (13,17,27). Additionally, the analog HL, an epimer of 1␣,25(OH) 2 D 3 (28), which is an antagonist of many membrane-initiated rapid effects of 1␣,25(OH) 2 D 3 , but not genomic effects (11), was able to prevent apoptosis when used either alone or in combination with JM or JN.…”

Section: Synthetic Vitamin D Analogs Exhibit Potent Anti-apoptotic Efmentioning

confidence: 99%

Nongenotropic, Anti-Apoptotic Signaling of 1α,25(OH)2-Vitamin D3 and Analogs through the Ligand Binding Domain of the Vitamin D Receptor in Osteoblasts and Osteocytes

Vertino

Bula

Chen

et al. 2005

Journal of Biological Chemistry

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Changes in the birth or death of osteoblasts and/or osteoclasts represent fundamental pathophysiologic changes in most acquired metabolic bone diseases, including the osteoporosis that results from sex steroid deficiency, glucocorticoid excess, or old age (1-6). Furthermore, pharmacotherapeutics used commonly for the treatment of metabolic bone diseases exert their beneficial effects on bone by regulating the rate of birth of new osteoclasts or osteoblasts or their apoptosis (6 -8).We have recently shown that estrogens and androgens, acting via their classical nuclear receptors (ER␣, 1 ER␤, or AR), attenuate the apoptosis of several different cell types, including osteoblasts and osteocytes, by rapidly activating the Src/Shc/ ERK and phosphatidylinositol 3-kinase (PI3K) and down-regulating the JNK signaling pathways. This effect requires only the ligand binding, not the DNA binding, domain of the receptor, and, unlike its classical transcriptional action, it is eliminated by nuclear targeting of the receptor (9). Activation of ERKs leads to the rapid translocation of the kinases into the nucleus where they phosphorylate common transcription factors like Elk-1, CCAAT enhancer-binding protein-␤, and cAMPresponse element-binding protein. These transcription factors in turn up-regulate gene expression, as exemplified by the up-regulation of the early growth response-1 protein gene, an ERK/serum response element target gene. Likewise, suppression of the JNK signaling cascade by sex steroids leads to downregulation of c-Jun expression (10). We have earlier used a ligand that potently and selectively activates nongenotropic actions of the classical ER or AR and thereby activates kinases and their downstream transcription factors and target genes with only minimal effects on classical estrogen response element-mediated genotropic transcription. Furthermore, we have demonstrated that, although such classical genotropic actions of sex steroid receptors are essential for their effects on reproductive tissues, they are dispensable for their bone protective effects (2).

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“…are also able to stimulate separate pathways, with structural confirmation and side chain additions or subtractions affecting the ability of the analog to bind to VDR or stimulate Ca 2ϩ influx (33)(34)(35)(36).…”

Section: Nifedipine Inhibits the 125-(oh) 2 D 3 -Induced Phosphorylamentioning

confidence: 99%

Modulation of Osteopontin Post-translational State by 1,25-(OH)2-Vitamin D3

Safran

Butler

Farach-Carson

1998

Journal of Biological Chemistry

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Osteopontin (OPN) 1 is a non-collagenous, glycosylated phosphoprotein originally found in bone matrix (1, 2), but now known to be expressed in many tissues including kidney, hypertrophic chondrocytes, placenta, T-lymphocytes, macrophages, secretory epithelia and ganglia of the inner ear, and smooth muscle of the vascular system (3, 4). OPN is also found in biological fluids such as milk (5), urine (6), and plasma (7), and it displays elevated expression in many transformed cells (8). OPN is highly acidic with approximately 25% of the amino acid composition aspartate and glutamate and significant numbers of phosphoserine and phosphothreonine (1, 2). The amino acid sequence contains a conserved Gly-Arg-Gly-Asp-Ser (GRGDS) sequence (2, 3). As a result, OPN binds effectively to the ␣ V ␤ 3 integrin (9), as well as to the ␣ V ␤ 5 and ␣ V ␤ 1 integrins (10). OPN also contains a thrombin cleavage site located near the middle of the molecule. Both peptides produced by thrombin cleavage are capable of supporting integrin-mediated cell attachment (11). Potential roles for OPN function through the ␣ V ␤ 3 integrin were proposed (12). OPN can promote attachment of various cell types and can initiate signal transduction through integrin-associated kinases. Other proposed roles for OPN include chemotaxis (13, 14), inhibition of nitric oxide synthase expression (15), activation of pp60 c-src (16), hydroxyapatite binding (17), and Ca 2ϩ binding (18). Hormone regulation plays an important role in OPN production. Our laboratory has examined the effect of the seco-steroid hormone 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) on OPN expression and secretion. After uptake of 1,25-(OH) 2 D 3 into a cell, the hormone binds to the vitamin D receptor (VDR), translocates to the nucleus, dimerizes preferentially with the retinoid X receptor, then binds to the vitamin D response element (VDRE) located in the promoter region of 1,25-(OH) 2 D 3 -responsive genes (19). In the case of OPN, this results in increased transcription as seen by higher OPN mRNA steady state levels at 24 -48 h (20) and, eventually, higher secreted protein levels (21). The OPN gene in rat is regulated by the additive action of two VDREs (3), which respond to both 1,25-(OH) 2 D 3 and to bioactive analogs of 1,25-(OH) 2 D 3 that bind to nuclear receptors (20).1,25-(OH) 2 D 3 regulation also occurs through rapid plasma membrane-initiated responses, which have been well studied in osteoblasts. We previously reported the 1,25-(OH) 2 D 3 regulation of L-type voltage-sensitive calcium channels (VSCC) in ROS 17/2.8 osteosarcoma cells (22,23 activates other osteoblast signaling pathways that are independent of transcription such as a rapid increase in phospholipase C activity (24), activation of protein kinase C (25), and regulation of whole cell chloride currents (26).In this publication, we report the effect of 1,25-(OH) 2 D 3 on osteoblast-like ROS 17/2.8 cells at a time period between the classic genomic response and the rapid membrane-associated responses. Examination of O...

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Comparison of 6-s-cis- and 6-s-trans-Locked Analogs of 1α,25-Dihydroxyvitamin D3 Indicates That the 6-s-cis Conformation Is Preferred for Rapid Nongenomic Biological Responses and That Neither 6-s-cis- nor 6-s-trans-Locked Analogs Are Preferred for Genomic Biological Responses

Cited by 41 publications

References 54 publications

Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH) ₂ -vitamin D ₃ signaling

Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH) ₂ -vitamin D ₃ signaling

Nongenotropic, Anti-Apoptotic Signaling of 1α,25(OH)2-Vitamin D3 and Analogs through the Ligand Binding Domain of the Vitamin D Receptor in Osteoblasts and Osteocytes

Modulation of Osteopontin Post-translational State by 1,25-(OH)2-Vitamin D3

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Comparison of 6-s-cis- and 6-s-trans-Locked Analogs of 1α,25-Dihydroxyvitamin D3 Indicates That the 6-s-cis Conformation Is Preferred for Rapid Nongenomic Biological Responses and That Neither 6-s-cis- nor 6-s-trans-Locked Analogs Are Preferred for Genomic Biological Responses

Cited by 41 publications

References 54 publications

Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH) 2 -vitamin D 3 signaling

Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH) 2 -vitamin D 3 signaling

Nongenotropic, Anti-Apoptotic Signaling of 1α,25(OH)2-Vitamin D3 and Analogs through the Ligand Binding Domain of the Vitamin D Receptor in Osteoblasts and Osteocytes

Modulation of Osteopontin Post-translational State by 1,25-(OH)2-Vitamin D3

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Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH) ₂ -vitamin D ₃ signaling

Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH) ₂ -vitamin D ₃ signaling