Vitamin D and gonadal steroid-resistant New World primate cells express an intracellular protein which competes with the estrogen receptor for binding to the estrogen response element.

Chen, H; Arbelle, Jonathan E.; Gacad, Mercedes A.; Allegretto, Elizabeth A.; Adams, John S.

doi:10.1172/jci119210

Cited by 29 publications

(30 citation statements)

References 23 publications

(28 reference statements)

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“…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/steroid hormone response element-binding protein to be discovered.…”

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confidence: 92%

“…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).…”

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confidence: 99%

“…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).…”

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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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confidence: 92%

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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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“…Estrogen resistance in NWP is associated with the overexpression of two proteins, a nonreceptor-related estrogen response element (ERE)-binding protein (ERE-BP) (17, 18) and an intracellular estradiol-binding protein (IEBP) (19,20). ERE-BP is a member of hnRNPC-like family and acts to squelch estrogen receptor (ER)-ERE transactivation by competing with the ER for binding to ERE (16,17). IEBP is a member of the Hsp27 family and is overexpressed in female and male estrogen-resistant NWP cells and tissue (19).…”

mentioning

confidence: 99%

“…By contrast, vitamin D resistance in NWPs appears to be caused by aberrant expression of a dominantnegative-acting vitamin D response element-binding protein (VDRE-BP), the protein being homologous to human heterogeneous nuclear ribonucleoprotein A (hnRNPA) (16). Estrogen resistance in NWP is associated with the overexpression of two proteins, a nonreceptor-related estrogen response element (ERE)-binding protein (ERE-BP) (17,18) and an intracellular estradiol-binding protein (IEBP) (19,20). ERE-BP is a member of hnRNPC-like family and acts to squelch estrogen receptor (ER)-ERE transactivation by competing with the ER for binding to ERE (16,17).…”

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An Hsp27-related, Dominant-negative-acting Intracellular Estradiol-binding Protein

Chen

Hewison

et al. 2004

Journal of Biological Chemistry

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New World primates (NWPs) exhibit a compensated form of resistance to gonadal steroid hormones. We demonstrated recently that estrogen resistance in NWP cells was associated with the overexpression of two proteins, a nonreceptor-related, dominant-negative-acting estrogen response element (ERE)-binding protein (ERE-BP) and an intracellular estradiol-binding protein (IEBP). Based on the N-terminal sequences of tryptic fragments of IEBP isolated from a 17␤-estradiol (E 2 ) affinity column we cloned a full-length cDNA for IEBP from the estrogen-resistant NWP cell line, B95-8. Subsequent sequence analysis revealed 87% sequence identity between the deduced peptide for IEBP and human Hsp27. When hormone-responsive, wild-type Old World primate (OWP) cells were transiently transfected with IEBP cDNA, E 2 -directed ERE reporter luciferase activity was reduced by 50% compared with vector only-transfected OWP cells (p < 0.0018). When IEBP and ERE-BP were cotransfected, ERE promoter-reporter activity was reduced by a further 60% (p < 0.0001). Electrophoresis mobility shift analyses showed that IEBP neither bound to ERE nor competed with the estrogen receptor (ER) for binding to ERE. However, there was evidence of protein-protein interaction of IEBP and ER␣; IEBP was coimmunoprecipitated with anti-ER␣ antibody in wildtype cells stably transfected with IEBP. A specific interaction between ER␣ and IEBP was confirmed in glutathione S-transferase pull-down and yeast two-hybrid assays. Data indicate that the Hsp27-related IEBP interacts with the ligand binding domain of the ER␣. In summary, by inhibiting the ER␣-E 2 interaction, IEBP acts to squelch ER␣-directed ERE-regulated transactivation and promote estrogen resistance in NWP cells.Compared with Old World primates (OWPs), 1 including man, New World primates (NWPs) represent an evolutionarily distinct infraorder of primates confined to the South and Central American subcontinents. A central point of distinction between NWPs and OWPs resides in the fact that NWPs display relative resistance to adrenal, gonadal, and vitamin D sterol/steroid hormones (1-11). The precise mechanism for this remains unclear but does not involve aberrant expression of nuclear receptors for specific steroid hormones (12, 13), the principal cause of hormone resistance in humans (14). Instead, hormone resistance in NWP cells appears to be the result of epigenetic factors, which result either in low affinity receptorsteroid binding kinetics or attenuation of receptor-DNA interaction. For example, studies of glucocorticoid resistance in NWP cells have shown increased expression of the heat shock protein (Hsp)90-associated FK506-binding immunophilin FKBP51, which inhibits ligand binding to glucocorticoid receptors (GR) (15). By contrast, vitamin D resistance in NWPs appears to be caused by aberrant expression of a dominantnegative-acting vitamin D response element-binding protein (VDRE-BP), the protein being homologous to human heterogeneous nuclear ribonucleoprotein A (hnRNPA) (16). Estrogen resistance in ...

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Cloning, sequencing, and functional characterization of the vitamin D receptor in vitamin D‐resistant New World primates

Chun

Chen

Boldrick³

et al. 2001

American J Primatol

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New World primates (NWPs) have high circulating 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels. Comparable levels would be harmful to Old World primates (OWPs) and humans. Thus, NWPs must have developed mechanisms of 1,25-(OH)2D resistance to survive. In humans, patients with hypocalcemic vitamin D-resistant rickets type II have high circulating vitamin D levels and vitamin D resistance due to expression of a dysfunctional vitamin D receptor (VDR). To examine if this could wholly or in part explain vitamin D resistance in NWPs, VDR from Saguinus oedipus (cotton top tamarin) NWP B95-8 cells was cloned by reverse-transcription polymerase chain reaction (RT-PCR). The NWP VDR cDNA sequence showed 96% homology at the DNA level and 98% homology at the amino acid level compared to human VDR. To assay for function, NWP VDR cDNA was transiently transfected into CV-1 cells with a vitamin D response element reporter plasmid. No difference between OWP and NWP VDR-directed transactivation was observed. These results indicate that the mechanism of vitamin D resistance in NWPs is not due to a dysfunctional VDR, and is consistent with our hypothesis that vitamin D resistance in NWPs is mediated by overexpression of a VDR-independent vitamin D response element binding protein.

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Vitamin D and gonadal steroid-resistant New World primate cells express an intracellular protein which competes with the estrogen receptor for binding to the estrogen response element.

Cited by 29 publications

References 23 publications

The Vitamin D Response Element-binding Protein

The Vitamin D Response Element-binding Protein

An Hsp27-related, Dominant-negative-acting Intracellular Estradiol-binding Protein

Cloning, sequencing, and functional characterization of the vitamin D receptor in vitamin D‐resistant New World primates

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