The Salk Institute for Biological Studies

Other

Arch Development Corporation

Bruce Blumberg

Ronald Mark Evans

Marianne E Greene

Barry M Forman

Estelita S Ong

Kazuhiko Umesono

Steven A Kliewer

Wen Xie

A novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), a broad-specificity sensing receptor that is a novel branch of the nuclear receptor superfamily, has been discovered. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P450 genes in response to hundreds of natural and synthetic compounds with biological activity, including therapeutic steroids as well as dietary steroids and lipids. Instead of hundreds of receptors, one for each inducing compound, the invention SXR receptors monitor aggregate levels of inducers to trigger production of metabolizing enzymes in a coordinated metabolic pathway. Agonists and antagonists of SXR are administered to subjects to achieve a variety of therapeutic goals dependent upon modulating metabolism of one or more endogenous steroids or xenobiotics to establish homeostasis. An assay is provided for identifying steroid drugs that are likely to cause drug interaction if administered to a subject in therapeutic amounts. Transgenic animals are also provided which express human SXR, thereby serving as useful models for human response to various agents which potentially impact P450-dependent metabolic processes.

Steroid-activated nuclear receptors and uses therefor

The invention relates generally to compositions of and methods for obtaining peroxisome proliferator-activated receptors. The invention relates as well to the DNA sequences encoding peroxisome proliferator-activated receptors, the recombinant vectors carrying those sequences, the recombinant host cells including either the sequences or vectors, and recombinant peroxisome proliferator-activated receptor polypeptides. By way of example, the invention discloses the cloning and functional expression of a peroxisome proliferator-activated receptor, designated PPAR-&#x3b3;, obtained from a human source. The invention includes as well, methods for using the isolated, recombinant peroxisome proliferator-activated receptor polypeptides in assays designed to select and improve substances capable of interacting with peroxisome proliferator-activated receptor polypeptides for use in diagnostic, drug design and therapeutic applications.

Human peroxisome proliferator activated receptor &#x3b3;: compositions and methods

Transgenic mice expressing a human SXR receptor polypeptide

The invention relates generally to compositions of and methods for obtaining peroxisome proliferator-activated receptors. The invention relates as well to the DNA sequences encoding peroxisome proliferator-activated receptors, the recombinant vectors carrying those sequences, the recombinant host cells including either the sequences or vectors, and recombinant peroxisome proliferator-activated receptor polypeptides. By way of example, the invention discloses the cloning and functional expression of a peroxisome proliferator-activated receptor, designated PPAR-&ggr;, obtained from a human source. The invention includes as well, methods for using the isolated, recombinant peroxisome proliferator-activated receptor polypeptides in assays designed to select and improve substances capable of interacting with peroxisome proliferator-activated receptor polypeptides for use in diagnostic, drug design and therapeutic applications.

Human peroxisome proliferator activated receptor &ggr; compositions and methods

A novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), a broad-specificity sensing receptor that is a novel branch of the nuclear receptor superfamily, has been discovered. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P450 genes in response to hundreds of natural and synthetic compounds with biological activity, including therapeutic steroids as well as dietary steroids and lipids. Instead of hundreds of receptors, one for each inducing compound, the invention SXR receptors monitor aggregate levels of inducers to trigger production of metabolizing enzymes in a coordinated metabolic pathway. Agonists and antagonists of SXR are administered to subjects to achieve a variety of therapeutic goals dependent upon modulating metabolism of one or more endogenous steroids or xenobiotics to establish homeostasis. An assay is provided for identifying steroid drugs that are likely to cause drug interaction if administered to a subject in therapeutic amounts.

In accordance with the present invention, there is provided an example of a novel class of nuclear receptor(s), termed the steroid X receptor (SXR). SXR is expressed almost exclusively in the liver, the primary site of xenobiotic and steroid catabolism. Unlike classical steroid receptors, SXR heterodimerizes with RXR and binds to directly repeated sequences related to the half-site, AGTTCA. SXR can activate transcription through response elements found in some steroid inducible P450 genes in response to a wide variety of natural and synthetic steroid hormones, including antagonists such as PCN&mdash;ideal properties for a &ldquo;steroid sensing receptor&rdquo; which mediates the physiological effect(s) of hormones. SXR represents the first new class of steroid receptors described since the identification of the mineralocorticoid receptor ten years ago. Also provided according to the invention are nucleic acid sequences encoding the above-identified receptors, as well as constructs and cells containing same, and probes derived therefrom. Furthermore, it has also been discovered that a wide variety of substrates modulate the transcription activating effects of invention receptors.

In accordance with the present invention, there are provided new members of the steroid receptor superfamily of receptors, a representative member of which has been designated XOR-6. Invention receptors are responsive to hydroxy, mercapto or amino benzoates, and are expressed, for example, in embryos. XOR-6 is most closely, although distantly, related to the vitamin D3 receptor (VDR). The proteins are about 73% identical in amino acid sequence in the DNA-binding domains and about 42% identical in the ligand binding domain. Like VDR, XOR-6 has an extended D region between the DNA and ligand binding domains. Notably, the region amino-terminal to the XOR-6 DNA-binding domain is extremely acidic. This may influence its ability to activate target genes. XOR-6 is not restricted to Xenopus because southern blots show the presence of XOR-6-related sequences in a variety of other vertebrates. Indeed, a human genomic clone for an XOR-6 related gene has recently been isolated. In accordance with a particular aspect of the present invention, there are also provided nucleic acid sequences encoding the above-identified receptor, as well as constructs and cells containing same, and probes derived therefrom. Furthermore, we have also discovered that hydroxy, mercapto or amino benzoates modulate the transcription activating effects of invention receptors.

Method, polypeptides, nucleotide sequence of XOR-6, a vitamin D-like receptor from xenopus

Human peroxisome proliferator activated receptor gamma: compositions and methods

Novel peroxisome proliferator-activated receptor subunits designated PPAR.gamma. and PPAR.delta. are described. Nucleic acid sequences encoding the receptor subunits, expression vectors containing such sequences and host cells transformed with such vectors are also disclosed, as are heterodimeric PPAR receptors comprising at least one of the invention subunits, and methods for the expression of such novel receptors, and various uses therefor.

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San Diego, CA, United States of America

Bruce Blumberg