Ligand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease

doi:10.1016/j.jsbmb.2011.04.007

The Journal of Steroid Biochemistry and Molecular Biology

Volume 130, Issues 3–5, July 2012, Pages 169-179

https://doi.org/10.1016/j.jsbmb.2011.04.007 Get rights and content

Abstract

DAX-1 and SHP are two closely related atypical orphan members of the nuclear receptor (NR) family that make up the NR0B subfamily. They combine properties of typical NRs and of NR-associated coregulators: both carry the characteristic NR ligand-binding domain but instead of a NR DNA-binding domain they have unique N-terminal regions that contain LxxLL-related NR-binding motifs often found in coregulators. Recent structural data indicate that DAX-1 lacks a ligand-binding pocket and thus should rely on ligand-independent mechanisms of regulation. This might be true, but remains to be proven, for SHP as well. DAX-1 and SHP have in common that they act as transcriptional corepressors of cholesterol metabolism pathways that are related on a molecular level. However, the expression patterns of the two NRs are largely different, with some notable exceptions, and so are the physiological processes they regulate. DAX-1 is mainly involved in steroidogenesis and reproductive development, while SHP plays major roles in maintaining cholesterol and glucose homeostasis. This review highlights the key similarities and differences between DAX-1 and SHP with regard to structure, function and biology and considers what can be learnt from recent research advances in the field.

This article is part of a Special Issue entitled ‘Orphan Receptors’.

Section snippets

A brief history of NR0B research

NR0B1, commonly known as DAX-1 (Dosage-sensitive sex reversal (DSS), Adrenal Hypoplasia Congenita (AHC) critical region on chromosome X, gene 1), derived its name from two syndromes caused by genetic alterations of the NR0B1 locus in humans. In DSS, a duplication of the DAX-1 gene locus causes XY-individuals to develop as females [5]. The study describing DSS initiated the discovery of the DAX-1 gene in 1994, which was recognized to encode an unusual NR family member. It was found that

Unique domain structure, molecular mechanisms and structural conundrums

The NR0B protein domain structure already reveals their unique place within the NR family. The classical NR is comprised of four typical domains, the N-terminal region, the DNA-binding domain (DBD) including two zinc-fingers and a dimerization surface, the hinge region and the ligand binding domain (LBD) with the ligand binding pocket (LBP) and coregulator binding surface. Of the 48 human NRs only two receptors break this pattern, DAX-1 and SHP (Fig. 1A). They lack the DBD and have instead

No pockets—no ligands?

LBD sequence homology classifies DAX-1 and SHP as true, albeit atypical, orphan members of the NR family. While it is believed that all LBD share a similar fold, individual crystal structures also have reveal important differences between the family members, which can explain some of their functional differences. The most striking example is the ligand-binding pocket (LBP), which differs greatly in size between the different receptors and, as a result, the ligands that can be accommodated in

NR0Bs and cholesterol metabolism: transcriptional feedback loops and the impact of post-translational modifications

Although both NR0Bs have restricted and distinct expression patterns, they have in common that they regulate pathways involved in cholesterol metabolism and homeostasis. DAX-1 with its expression in steroidogenic tissues of the HPA/G axis controls both the fetal development of these tissues and the expression of enzymes converting cholesterol to steroid hormones in adult life. SHP on the other hand seems less crucial during development but is at the hub of the regulatory network governing

DAX-1 in regulation of stem cell pluripotency

The first indications of DAX-1 being important for mouse embryonic stem cell pluripotency were the difficulties encountered in establishing a DAX-1 knock-out mouse model. Classical knock out strategy failed to generate undifferentiated embryonic stem cells and researchers had to use a cre-lox P recombination strategy instead [20]. Five years later Mitsui et al. identified DAX-1 as one of the transcripts highly expressed in ES cells compared to somatic cells [70] and further research revealed

NR0B in cancer—oncogenic versus tumor suppressor action

The first reports of the involvement of DAX-1 in cancers came from histological examination of tumors in the adrenal cortex. It was described that the levels of DAX-1 was inversely correlated to the level of steroid production in the tumors [75], [76], [77]. DAX-1 expression in breast [78], ovarian [79], endometrial [80] and prostate cancers [81] have also been reported but not investigated closely. The recent identification of SF-1 as a proliferative factor in childhood adrenocortical tumors

Where to go and what to expect in the future?

In case of SHP, additional physiological functions are still to be uncovered, since SHP mRNA appears also to be expressed in additional tissues linked to glucose homeostasis (e.g. pancreas) or reproduction and steroidogenesis (e.g. testis, adrenal). Furthermore, SHP expression appears to be controlled by a variety of signals including estrogens, cytokines, and molecular clock components, suggesting functions of SHP in finetuning of metabolic, reproductive and inflammatory pathways in a perhaps

Acknowledgements

We would like to thank Dr. Grzegorz Raszewski for help in analyzing the DAX-1 structure data and sequence alignments. This work was supported by grants from the Center for Biosciences, the Swedish Research Council, and the Swedish Cancer Society to ET.

References (132)

A. Bavner et al.
Transcriptional corepression by SHP: molecular mechanisms and physiological consequences
Trends Endocrinol. Metab.
(2005)
J.C. Achermann et al.
Phenotypic spectrum of mutations in DAX-1 and SF-1
Mol. Cell. Endocrinol.
(2001)
W. Guo et al.
Expression of DAX-1, the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism, in the hypothalamic–pituitary–adrenal/gonadal axis
Biochem. Mol. Med.
(1995)
M.W. Nachtigal et al.
Wilms’ tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression
Cell
(1998)
L.M. Halvorson
Transcriptional regulation of the LH beta gene by gonadotropin-releasing hormone and the protein kinase C system
Vitam. Horm.
(2000)
J. Ho et al.
NR0B1A: an alternatively spliced form of NR0B1
Mol. Genet. Metab.
(2004)
T.T. Lu et al.
Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors
Mol. Cell
(2000)
T.A. Kerr et al.
Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis
Dev. Cell
(2002)
L. Wang et al.
Redundant pathways for negative feedback regulation of bile acid production
Dev. Cell
(2002)
L. Wang et al.
Resistance of SHP-null mice to bile acid-induced liver damage
J. Biol. Chem.
(2003)

H.B. Hartman et al.

Loss of small heterodimer partner expression in the liver protects against dyslipidemia

J. Lipid Res.

(2009)

J. Sugita et al.

Expression of Dax-1 during gonadal development of the frog

Gene

(2001)

Y.Y. Park et al.

Distinct repressive properties of the mammalian and fish orphan nuclear receptors SHP and DAX-1

Mol. Cells

(2007)

G.V. Markov et al.

Origin and evolution of the ligand-binding ability of nuclear receptors

Mol. Cell. Endocrinol.

(2011)

M. Patel et al.

Primate DAX1, SRY, and SOX9: evolutionary stratification of sex-determination pathway

Am. J. Hum. Genet.

(2001)

L. Johansson et al.

The orphan nuclear receptor SHP inhibits agonist-dependent transcriptional activity of estrogen receptors ERalpha and ERbeta

J. Biol. Chem.

(1999)

H. Zhang et al.

DAX-1 functions as an LXXLL-containing corepressor for activated estrogen receptors

J. Biol. Chem.

(2000)

B. Altincicek et al.

Interaction of the corepressor Alien with DAX-1 is abrogated by mutations of DAX-1 involved in adrenal hypoplasia congenita

J. Biol. Chem.

(2000)

K.D. Baker et al.

The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway

Cell

(2003)

S. Dhe-Paganon et al.

Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand

J. Biol. Chem.

(2002)

G.B. Wisely et al.

Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids

Structure

(2002)

B. Goodwin et al.

A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis

Mol. Cell

(2000)

T.P. Burris et al.

Identification of a putative steroidogenic factor-1 response element in the DAX-1 promoter

Biochem. Biophys. Res. Commun.

(1995)

H.K. Lee et al.

Structure and expression of the orphan nuclear receptor SHP gene

J. Biol. Chem.

(1998)

Y.K. Lee et al.

Activation of the promoter of the orphan receptor SHP by orphan receptors that bind DNA as monomers

J. Biol. Chem.

(1999)

T. Inagaki et al.

Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis

Cell Metab.

(2005)

N. Blom et al.

Sequence and structure-based prediction of eukaryotic protein phosphorylation sites

J. Mol. Biol.

(1999)

K. Mitsui et al.

The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells

Cell

(2003)

K.K. Niakan et al.

Novel role for the orphan nuclear receptor Dax1 in embryogenesis, different from steroidogenesis

Mol. Genet. Metab.

(2006)

C. Sun et al.

Stem cell-specific expression of Dax1 is conferred by STAT3 and Oct3/4 in embryonic stem cells

Biochem. Biophys. Res. Commun.

(2008)

H. Shibata et al.

Expression profiles of COUP-TF, DAX-1, and SF-1 in the human adrenal gland and adrenocortical tumors: possible implications in steroidogenesis

Mol. Genet. Metab.

(2001)

M.A. Pianovski et al.

SF-1 overexpression in childhood adrenocortical tumours

Eur. J. Cancer

(2006)

T. Oda et al.

Tumorigenic role of orphan nuclear receptor NR0B1 in lung adenocarcinoma

Am. J. Pathol.

(2009)

N. He et al.

Epigenetic inhibition of nuclear receptor small heterodimer partner is associated with and regulates hepatocellular carcinoma growth

Gastroenterology

(2008)

E. Lalli et al.

DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation

Mol. Endocrinol.

(2003)

E. Lalli et al.

Targeting DAX-1 in embryonic stem cells and cancer

Expert Opin. Ther. Targets

(2010)

M.K. Kim et al.

Targeting orphan nuclear receptor SHP in the treatment of metabolic diseases

Expert Opin. Ther. Targets

(2010)

B. Bardoni et al.

A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal

Nat. Genet.

(1994)

E. Zanaria et al.

An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita

Nature

(1994)

F. Muscatelli et al.

Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism

Nature

(1994)

Z. Landau et al.

Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations

Clin. Endocrinol. (Oxf.)

(2010)

Y. Ikeda et al.

Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in endocrine development

Mol. Endocrinol.

(1996)

Y. Ikeda et al.

Comparative localization of Dax-1 and Ad4BP/SF-1 during development of the hypothalamic–pituitary–gonadal axis suggests their closely related and distinct functions

Dev. Dyn.

(2001)

E. Zazopoulos et al.

DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis

Nature

(1997)

E. Lalli et al.

DAX-1 blocks steroid production at multiple levels

Endocrinology

(1998)

N.A. Hanley et al.

Expression profiles of SF-1, DAX1, and CYP17 in the human fetal adrenal gland: potential interactions in gene regulation

Mol. Endocrinol.

(2001)

Z.J. Wang et al.

Aromatase (Cyp19) expression is up-regulated by targeted disruption of Dax1

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

(2001)

Y. Nakamura et al.

DAX-1A (NR0B1A) expression levels are extremely low compared to DAX-1 (NR0B1) in human steroidogenic tissues

Horm. Metab. Res.

(2009)

W. Seol et al.

An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors

Science

(1996)

K. Boulias et al.

Regulation of hepatic metabolic pathways by the orphan nuclear receptor SHP

EMBO J.

(2005)

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The LXXLL motifs mediate the homo- or hetero-dimerization of DAX1/SHP with various hNR members by specifically recognizing and interacting with the activation function-2 (AF-2) domain of their partner proteins [12,13]. Currently, a variety of DAX1/SHP-interacting partners have been identified in the human genome, including NUR77, CAR, SF1 and LRH1; they are involved in diverse physiological functions and pathological processes, such as xenobiotic metabolism, subcellular localization, idiopathic azoospermia, and adrenal hypoplasia congenital [14]. Over the past decades, drugs have been traditionally developed to target druggable proteins.
The atypical orphan receptors DAX1 and SHP constitute the NR0B subgroup of human nuclear receptor (hNR) family; they play key roles in metabolism, reproduction, nutrition and steroidogenesis, and are involved in the pathogenesis of a variety of diseases such as cancer and adrenal hypoplasia. The two receptors lack the classical DNA-binding domain and act as the corepressors of other hNRs. The DAX1 and SHP contains three and two conserved LXXLL motifs, respectively, which can be recognized and bound by the activation function-2 (AF-2) domain of hNR proteins in agonist conformation. Here, we attempt to explore the systematic interaction profile between the five DAX1/SHP LXXLL motifs and all the 48 hNR AF-2 domains found in the human genome, to analyze the binding affinity and specificity of these motifs towards the complete domain array, and to design LXXLL-based, hydrocarbon-stapled peptides that can target the specific interaction profile for each motif. A weighted source–target network from motifs to domains is created based on the modeled domain–motif complex structures and calculated binding potencies, from which the specific interaction profile of each motif against the whole hNR array is depicted and clustered to measure the binding similarity and relationship among these motifs. Dynamics simulations reveal that the LXXLL-based peptides are highly flexible in free unbound state, thus unfavorable to be recognized and bound by AF-2 domains. Hydrocarbon-stapling technique is employed to help the constraint of these unstructured peptides to active helical conformation, thus largely improving their binding affinity to the hNR array. The hydrocarbon bridge is designed to point out of the domain's active pocket, which would not disrupt the direct interaction between the domain and peptide. Energetic decomposition imparts that the stapling has only a very modest influence on the interaction enthalpy and desolvation effect of domain–peptide binding, but can substantially reduce entropy penalty upon the binding. For a peptide ligand, the entropic reduction can be roughly regarded as a constant, which only improves (absolute) peptide binding affinity towards the whole domain array, but does not alter (relative) peptide binding specificity over different domains in the array. Overall, the stapled peptides can be considered as potent competitors to selectively target the specific interaction networks mediated by their parent LXXLL motifs in DAX1 and SHP proteins.
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This article is part of a Special Issue entitled ‘Orphan Nuclear Receptors’.

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ReviewLigand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease

Abstract

Section snippets

A brief history of NR0B research

Unique domain structure, molecular mechanisms and structural conundrums

No pockets—no ligands?

NR0Bs and cholesterol metabolism: transcriptional feedback loops and the impact of post-translational modifications

DAX-1 in regulation of stem cell pluripotency

NR0B in cancer—oncogenic versus tumor suppressor action

Where to go and what to expect in the future?

Acknowledgements

Trends Endocrinol. Metab.

Mol. Cell. Endocrinol.

Biochem. Mol. Med.

Cell

Vitam. Horm.

Mol. Genet. Metab.

Mol. Cell

Dev. Cell

Dev. Cell

J. Biol. Chem.

J. Lipid Res.

Gene

Mol. Cells

Mol. Cell. Endocrinol.

Am. J. Hum. Genet.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

Structure

Mol. Cell

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Cell Metab.

J. Mol. Biol.

Cell

Mol. Genet. Metab.

Biochem. Biophys. Res. Commun.

Mol. Genet. Metab.

Eur. J. Cancer

Am. J. Pathol.

Gastroenterology

DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation

Mol. Endocrinol.

Targeting DAX-1 in embryonic stem cells and cancer

Expert Opin. Ther. Targets

Targeting orphan nuclear receptor SHP in the treatment of metabolic diseases

Expert Opin. Ther. Targets

A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal

Nat. Genet.

An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita

Nature

Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism

Nature

Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations

Clin. Endocrinol. (Oxf.)

Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in endocrine development

Mol. Endocrinol.

Comparative localization of Dax-1 and Ad4BP/SF-1 during development of the hypothalamic–pituitary–gonadal axis suggests their closely related and distinct functions

Dev. Dyn.

DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis

Nature

DAX-1 blocks steroid production at multiple levels

Endocrinology

Expression profiles of SF-1, DAX1, and CYP17 in the human fetal adrenal gland: potential interactions in gene regulation

Mol. Endocrinol.

Aromatase (Cyp19) expression is up-regulated by targeted disruption of Dax1

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

DAX-1A (NR0B1A) expression levels are extremely low compared to DAX-1 (NR0B1) in human steroidogenic tissues

Horm. Metab. Res.

An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors

Science

Regulation of hepatic metabolic pathways by the orphan nuclear receptor SHP

EMBO J.

Review
Ligand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease