Adaptation of the Mineralocorticoid Target Tissues to the High Circulating Cortisol and Progesterone Plasma Levels in the Squirrel Monkey<sup>*</sup>

Chrousos, George P.; Loriaux, D. Lynn; Brandon, David D.; Shull, James H.; Renquist, D; Hogan, William C.; Tomita, Mizuki; Lipsett, Mortimer B.

doi:10.1210/endo-115-1-25

Cited by 60 publications

(14 citation statements)

References 36 publications

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“…The existence of steroid hormone-resistant states in monkeys from the New World was first described by Chrousos and his colleagues (29). They reported high circulating levels of adrenal (29 -31) and gonadal (32) steroids in NWP from several different genera.…”

Section: Discussionmentioning

confidence: 95%

Functional Characterization and Purification of an Intracellular Vitamin D-binding Protein in Vitamin D-resistant New World Primate Cells

Gacad

Chen

Arbelle

et al. 1997

Journal of Biological Chemistry

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(8, 9). Unlike the cysteine-rich sterol/steroid-binding proteins in serum vitamin D-binding protein/albumin (9) and vitamin D/steroid receptor protein (10) families, which are confined prinicipally to the extracellular domain and nucleus, respectively, IDBP is a relatively abundant, cysteine-poor protein concentrated in, but not confined to, the cytoplasmic compartment of cells (11). However, like these other sterol/steroidbinding proteins (8,9), IDBP has been shown preferentially to bind 25-hydroxylated vitamin D metabolites (12). In the current report we have greatly expanded the vitamin D metabolite-IDBP binding studies to define more clearly which structural modifications of the vitamin D molecule are important for either enhancing or reducing ligand binding to IDBP extracted from NWP cells. We also document the IDBP binding potential of a much more extensive panel of molecules in an attempt to define additional classes of small, lipid-soluble signaling molecules which may interact with IDBP. Although we were previously able to enrich vitamin D metabolite binding activity in extracts of NWP cells (13), attempts to purify IDBP to homogeneity were unsuccessful. Here we report the purification and structural identification of the NWP IDBP as a member of the hsp-70 family of proteins and demonstrate the sterol/steroid binding properties of hsp-70-like proteins. D Sterols, Steroids, 3 H]Hydroxyvitamin D 3 (25-[ 3 H]OHD 3 ; specific activity, 181 Ci/mmol) and MATERIALS AND METHODS Vitamin

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Section: Discussionmentioning

confidence: 95%

Functional Characterization and Purification of an Intracellular Vitamin D-binding Protein in Vitamin D-resistant New World Primate Cells

Gacad

Chen

Arbelle

et al. 1997

Journal of Biological Chemistry

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“…Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a family of Ͼ20 proteins that contributes to the complex around nascent pre-mRNA and are thus able to modulate RNA processing (10)(11)(12). The ability of hnRNPs to attenuate steroid hormone receptor gene transactivation has been demonstrated in studies of New World primates (NWPs) that are characterized by their relative target organ resistance to adrenal, gonadal, and vitamin D sterol͞steroid hormones (13)(14)(15)(16)(17)(18)(19)(20). Data indicate that NWPs exhibit forms of receptor-normal resistance to vitamin D and estrogen that are due to overexpression of hnRNP-like dominant-negative-acting hormone response element (RE)-binding proteins (REBiPs; refs.…”

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confidence: 99%

Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: A cause of vitamin D resistance

Chen

Hewison

et al. 2003

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

125

108

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In previous studies, we have shown that steroid hormone resistance in New World primates occurs in the absence of abnormal expression of cognate nuclear receptors. Rather, these animals have elevated levels of heterogeneous nuclear ribonucleoproteins (hnRNPs) that act as hormone response element-binding proteins and attenuate target gene transactivation. Here we present evidence for a similar mechanism in humans via a patient with resistance to the active form of vitamin D [1,25-dihydroxyvitamin D3 (1,25(OH)2D3)] who presented with normal vitamin D receptor (VDR) expression. Initial cotransfection studies showed that the cells of the patient suppressed basal and hormone-induced transactivation by wild-type VDR. Electrophoretic mobility-shift assays and Western͞Southwestern blot analyses indicated that this suppressive effect was due to overexpression of a nuclear protein that specifically interacts with a DNA response element known to bind retinoid X receptor-VDR heterodimers. Ab blocking in electrophoretic mobility-shift assays indicated that this dominant-negative acting protein was in the hnRNPA family of nucleic acid-binding proteins. Further studies have shown that several members of this family, most notably hnRNPA1, were able to suppress basal and 1,25(OH)2D3-induced luciferase activity. We therefore propose that this case of vitamin D resistance in a human subject is similar to that previously described for New World primates in which abnormal expression of a hormone response element-binding protein can cause target cell resistance to 1,25(OH)2D3. That this protein is a member of the hnRNP family capable of interacting with doublestranded DNA highlights a potentially important new component of the complex machinery required for steroid hormone signal transduction.A nalysis of inherited forms of steroid hormone resistance has greatly helped to clarify the underlying mechanisms by which molecules such as cortisol, testosterone, estradiol, and vitamin D achieve their actions (1, 2). In almost all cases, end organ resistance has been attributed to inactivating mutations of genes for intracellular steroid hormone receptors, despite the fact that a range of accessory proteins is required for steroid hormone signal transduction (3-5). However, recent reports have described novel forms of hormone resistance that have presented in the absence of a specific receptor gene mutation. These include an androgen receptor (AR)-positive patient with androgen insensitivity syndrome whose hormone resistance seems to be due to abnormal expression of a coactivator protein that interacts with the AF-1 domain of the AR (6). Accessory protein abnormality has also been proposed as the molecular defect in female siblings who presented with partial resistance to multiple steroid hormones (7). In view of these observations, it is possible to speculate that other forms of hormone resistance may also be due to abnormal accessory protein expression and function (8,9).We have shown that another class of proteins possibly acts as dominan...

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“…Squirrel monkeys, cotton-top tamarins, and owl monkeys have markedly elevated plasma cortisol levels, but they show no signs of glucocorticoid excess (5,6). They have been proposed as models for the in vivo study of glucocorticoid sensitivity (3,5).…”

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confidence: 99%

Glucocorticoid Resistance in the Squirrel Monkey Is Associated with Overexpression of the Immunophilin FKBP51¹

Reynolds¹,

Ruan²,

Smith³

et al. 1999

The Journal of Clinical Endocrinology & Metabolism

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Squirrel monkeys are neotropical primates that have high circulating cortisol to compensate for expression of glucocorticoid receptors (GRs) with reduced affinity. The low binding affinity of squirrel monkey GR does not result from substitutions in the receptor, because squirrel monkey GR expressed in vitro exhibits high affinity. Rather, squirrel monkeys express a soluble factor that, in mixing studies of cytosol from squirrel monkey lymphocytes (SML) and mouse L929 cells, reduced GR binding affinity by 11-fold. In an effort to identify this factor, the cellular levels of components of the GR heterocomplex in SML and human lymphocytes (HL) were compared. The immunophilin FKBP51 was 13-fold higher in SML than in HL cytosol; FKBP52 in SML was 42% of that in HL cytosol. A role for changes in immunophilins, causing glucocorticoid resistance in neotropical primates, is supported by the following: the changes in FKBP51 and FKBP52 were observed in cells from other neotropical primates with glucocorticoid resistance; the elevated level of FKBP51 was reflected in an abundance of FKBP51 in heat shock protein 90 complexes in SML; when cytosols of SML and L929 cells were mixed, the decrease in GR binding was associated with incorporation of FKBP51 into GR heterocomplexes; the effect of SML cytosol on GR binding was reproduced with cytosol from COS cells expressing squirrel monkey FKBP51; and both the effect of SML cytosol on GR binding and the incorporation of FKBP51 into GR heterocomplexes were blocked by FK506. Regulation of GR binding by FKBP51 represents a previously unrecognized mechanism for regulating glucocorticoid sensitivity. (J Clin Endocrinol Metab 84: [663][664][665][666][667][668][669] 1999) G LUCOCORTICOIDS play an essential role in regulating many developmental and physiological processes (1). The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a member of the steroid hormone receptor superfamily (2). The GR protein is made up of an aminoterminal transactivation domain, a central DNA-binding domain, and a carboxyterminus that includes the ligandbinding domain and sequences involved in interaction with heat shock proteins (hsps) (3). In the unliganded state, the GR resides in the cytoplasm associated with hsps and other chaperone proteins, forming a multiprotein complex (4). The ordered association of chaperone complexes with the GR is critical in establishing a receptor conformation optimally responsive to hormone (4).Our recent studies have focused on the mechanisms of glucocorticoid insensitivity in species of neotropical primates. Squirrel monkeys, cotton-top tamarins, and owl monkeys have markedly elevated plasma cortisol levels, but they show no signs of glucocorticoid excess (5, 6). They have been proposed as models for the in vivo study of glucocorticoid sensitivity (3, 5). Chrousos et al. (5) demonstrated a greater than 20-fold higher apparent dissociation constant for the GR in squirrel monkey mononuclear leukocytes than in human cells, suggesting that a dec...

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Adaptation of the Mineralocorticoid Target Tissues to the High Circulating Cortisol and Progesterone Plasma Levels in the Squirrel Monkey^*

Cited by 60 publications

References 36 publications

Functional Characterization and Purification of an Intracellular Vitamin D-binding Protein in Vitamin D-resistant New World Primate Cells

Functional Characterization and Purification of an Intracellular Vitamin D-binding Protein in Vitamin D-resistant New World Primate Cells

Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: A cause of vitamin D resistance

Glucocorticoid Resistance in the Squirrel Monkey Is Associated with Overexpression of the Immunophilin FKBP51¹

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Adaptation of the Mineralocorticoid Target Tissues to the High Circulating Cortisol and Progesterone Plasma Levels in the Squirrel Monkey*

Cited by 60 publications

References 36 publications

Functional Characterization and Purification of an Intracellular Vitamin D-binding Protein in Vitamin D-resistant New World Primate Cells

Functional Characterization and Purification of an Intracellular Vitamin D-binding Protein in Vitamin D-resistant New World Primate Cells

Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: A cause of vitamin D resistance

Glucocorticoid Resistance in the Squirrel Monkey Is Associated with Overexpression of the Immunophilin FKBP511

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Adaptation of the Mineralocorticoid Target Tissues to the High Circulating Cortisol and Progesterone Plasma Levels in the Squirrel Monkey^*

Glucocorticoid Resistance in the Squirrel Monkey Is Associated with Overexpression of the Immunophilin FKBP51¹