Endogenous blockade of 1,25-dihydroxyvitamin D-receptor binding in New World primate cells.

Gacad, Mercedes A.; Adams, John S.

doi:10.1172/jci115108

Cited by 44 publications

(33 citation statements)

References 33 publications

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“…NWPs are also profoundly resistant to vitamin D. As with glucocorticoids, this appears to be due to impaired signaling via the cognate intracellular receptor, in this case the VDR. Initial studies suggested that the blockade of VDR action in NWPs was due to the elevated levels of a soluble protein that could act as a competitor for binding of 1,25(OH) 2 D (Gacad & Adams 1991, 1992. The purification of this intracellular DBP (IDBP) revealed similarity to the constitutively expressed human heat-shock protein 70 (hsc70) , and also indicated that hsc70 was capable of binding both 25OHD and 1,25(OH) 2 D, as well as gonadal steroids such as estradiol ).…”

Section: Primate Responses To Vitamin D Metabolites: New World Versusmentioning

confidence: 99%

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Back to the future: a new look at ‘old’ vitamin D

Chun¹,

Adams²,

Hewison³

2008

Journal of Endocrinology

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Our perception of the vitamin D system continues to evolve. Recent studies have re-evaluated the parameters for adequate vitamin D status in humans, revealing a high prevalence of insufficiency in many populations throughout the world. Other reports have highlighted the potential consequences of vitamin D insufficiency beyond established effects on bone homeostasis. Most notably, there is now strong evidence of a role for vitamin D in modulating innate and adaptive immunities, with insufficiency being linked to infectious disease and other immune disorders. To date, signaling pathways for these new responses to vitamin D have been based on established endocrine models for active 1,25-dihydroxyvitamin D, despite present evidence for more localized, intracrine modes of action. In the following review, we provide a fresh perspective on vitamin D signaling in nonclassical target cells such as macrophages by highlighting novel factors associated with the transport and action of this pluripotent secosteroid.

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Section: Primate Responses To Vitamin D Metabolites: New World Versusmentioning

confidence: 99%

“…As outlined above, decreased VDR function in NWPs involves diminished nuclear activity of the liganded receptor (Gacad & Adams 1991). This was initially attributed to the elevated levels of IDBPs in NWPs, which were thought to act as decoy-binding sites for 1,25(OH) 2 D .…”

Section: Vdre-binding Proteins (Vdre-bps) and The Regulation Of Vdr-imentioning

confidence: 99%

Back to the future: a new look at ‘old’ vitamin D

Chun¹,

Adams²,

Hewison³

2008

Journal of Endocrinology

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“…Another proposed microregulator in the vitamin D metabolism/action system is the newly discovered family of hsp70-related intracellular vitamin D-binding proteins. These proteins, initially identified in vitamin D-resistant New World primate cells (52,53), have a high capacity and relatively high affinity (2-20 nM) for 25-hydroxylated vitamin D metabolites (54). Recent work 2 indicates that these proteins have the ability to facilitate hormone action by delivery of 1,25-dihydroxyvitamin D hormone to the nucleus and VDR, which has a higher affinity for hormone than the intracellular vitamin D-binding proteins.…”

Section: Discussionmentioning

confidence: 99%

“…The partially hormone-responsive New World primate ge-3 H. Chen, unpublished data. nus Aotus and the hormone-resistant New World primate genus Callithrix (52) are respective examples of the micro-and macroregulatory phenotype. Because Aotus cells express relatively little mRNA (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, Callithrix, which expresses high levels of the VDRE-BP mRNA and protein (Figs. 3C and 6A), possesses very high serum levels of 1,25-dihydroxyvitamin D and an extreme propensity to develop rickets when cutaneous vitamin D synthesis is challenged (19,20,52). Are there human equivalents to the microregulatory and macroregulatory phenotypes caused by the VDRE-BPs in subhuman primates?…”

Section: Discussionmentioning

confidence: 99%

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The Vitamin D Response Element-binding Protein

Chen¹,

Hu²,

Allegretto³

et al. 2000

Journal of Biological Chemistry

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Vitamin D resistance in certain primate genera is associated with the constitutive overexpression of a nonvitamin D receptor (VDR)-related, vitamin D response element-binding protein (VDRE-BP) and squelching of vitamin D-directed transactivation. We used DNA affinity chromatography to purify proteins associated with non-VDR-VDRE binding activity from vitamin D-resistant New World primate cells. In electrophoretic mobility shift assays, these proteins bound specifically to either single-strand or double-strand oligonucleotides harboring the VDRE. Amino acid sequencing of tryptic peptides from a 34-kDa (VDRE-BP1) and 38-kDa species (VDRE-BP-2) possessed sequence homology with human heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and hnRNPA2, respectively. cDNAs bearing the open reading frame for both VDRE-BPs were cloned and used to transfect wild-type, hormone-responsive primate cells. Transient and stable overexpression of the VDRE-BP2 cDNA, but not the VDRE-BP1 cDNA, in wild-type cells with a VDRE-luciferase reporter resulted in significant reduction in reporter activity. These data suggest that the hnRNPA2-related VDRE-BP2 is a dominantnegative regulator of vitamin D action. Dominant-negative control of steroid hormone-regulated gene transcription has been traditionally attributed to: 1) expression of transcriptionally silent receptor molecules, which compete with transactivating receptor dimer pairs for binding to enhancer elements (1, 2); and 2) expression of non-DNAbinding co-repressor molecules, which interact with other constituents of the transcriptional complex to halt or slow transcription (3). More recently, another family of dominantnegative-acting proteins which squelch transcription have been identified. These proteins are in the heterogeneous nuclear ribonuclear protein (hnRNP) 1 superfamily (4 -8). hnRNPs were initially recognized for their ability to bind to singlestrand pre-mRNA (9, 10) and control the modification and movement of mRNA in the cell. The fact that hnRNPs could function as dominant-negative regulators of transcription was discovered in New World primates, a nonhuman primate suborder that is characterized phenotypically by relative targettissue resistance to adrenal, gonadal, and vitamin D sterol/ steroid hormones (11)(12)(13)(14)(15)(16)(17)(18)(19)(20).We recently cloned and characterized the first member of the hnRNP family capable of modifying steroid hormone-directed transactivation (21,22), the estrogen response element-binding protein (ERE-BP). The 42-kDa ERE-BP is highly homologous to proteins in the hnRNPC subfamily (23). It acts to squelch estrogen receptor (ER)-estrogen response element (ERE)-directed transactivation by competing with the ER homodimer for binding to the ERE. Although discovered because of its overexpression in estrogen-resistant New World primate species, the ERE-BP is also expressed in Old World primate species including man (21). The vitamin D response elementbinding protein or VDRE-BP described here is in the second set of non-receptor sterol/stero...

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Assessing vitamin D status of callitrichids: Baseline data from wild cotton-top tamarins (Saguinus oedipus) in Colombia

et al. 1997

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Bone disease related to vitamin D deficiency is an insidious problem in captive colonies of callitrichids. Currently a diagnosis of vitamin D deficiency may be made after the appearance of clinical pathology, usually bone deformities or fractures. The development of assays for vitamin D metabolites suggests it may be possible to detect incipient vitamin D deficiency before animals are adversely affected. However, there are few data on normative levels of these metabolites in any nonhuman primates. We collected blood samples from 18 wild cotton‐top tamarins (Saguinus oedipus) from Colombia and assayed them for 25‐hydroxy vitamin D(25‐OH‐D), the major circulating form of the vitamin, which is believed to be a good indicator of status. Serum concentrations of 25‐OH‐D averaged 76.4 ng/ml (range 25.5–120 ng/ml). This is high compared with human norms (10–55 ng/ml), but the range is lower than that reported in the literature for captive callitrichids. Juveniles had higher serum concentrations than did adults, and pregnant females had lower concentrations than did nonpregnant females. These data confirm that healthy callitrichids have higher circulating levels of 25‐OH‐D than do humans, but they suggest that the extremely high levels found in some captive animals (300–600 ng/ml) may be above normal. We propose that serum concentrations of 25‐OH‐D of 50–120 ng/ml can be considered normal for cotton‐top tamarins and perhaps other callitrichids. If serum values much below 50 ng/ml are found during clinical evaluation, the possibility of incipient vitamin D deficiency should be considered. Zoo Biol 16:39–46, 1997. © 1997 Wiley‐Liss, Inc.

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Endogenous blockade of 1,25-dihydroxyvitamin D-receptor binding in New World primate cells.

Abstract: When assessed by 1,25(OH) Clin. Invest. 1991. 87:996-1001

Cited by 44 publications

References 33 publications

Back to the future: a new look at ‘old’ vitamin D

Back to the future: a new look at ‘old’ vitamin D

The Vitamin D Response Element-binding Protein

Assessing vitamin D status of callitrichids: Baseline data from wild cotton-top tamarins (Saguinus oedipus) in Colombia

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