Nuclear receptors regulate metabolic pathways in response to changes in the environment by appropriate alterations in gene expression of key metabolic enzymes. Here, a computational search approach based on iteratively built hidden Markov models of nuclear receptors was used to identify a human nuclear receptor, termed hPAR, that is expressed in liver and intestines. hPAR was found to be efficiently activated by pregnanes and by clinically used drugs including rifampicin, an antibiotic known to selectively induce human but not murine CYP3A expression. The CYP3A drugmetabolizing enzymes are expressed in gut and liver in response to environmental chemicals and clinically used drugs. Interestingly, hPAR is not activated by pregnenolone 16␣-carbonitrile, which is a potent inducer of murine CYP3A genes and an activator of the mouse receptor PXR.1. Furthermore, hPAR was found to bind to and trans-activate through a conserved regulatory sequence present in human but not murine CYP3A genes. These results provide evidence that hPAR and PXR.1 may represent orthologous genes from different species that have evolved to regulate overlapping target genes in response to pharmacologically distinct CYP3A activators, and have potential implications for the in vitro identification of drug interactions important to humans.The recent progress made in determining the full genomic sequences of model organisms as well as the rapid accumulation of sequence data from the human genome has opened up new possibilities to determine the functional organization of genomes by computational approaches (1). Multiple alignments of members of different protein families followed by homology searching are powerful methods to infer gene function from sequence data as well as to identify novel genes within a given gene family. Hidden Markov models (HMMs) are a general statistical modeling technique that can be used as formal, fully probabilistic forms of sequence profiles (2, 3), describing the consensus of a set of sequences. This approach toward the identification and functional characterization of novel genes is particularly amenable to evolutionary conserved gene families consisting of a large number of orthologs and paralogs. The nuclear receptors constitute one such large gene family that is structurally and functionally conserved and represented within different metazoan phylae from cnidarians to vertebrates (4). These receptors are conditionally regulated transcription factors that exert their effects by interacting with small lipophilic ligands followed by sequence-specific binding of the receptor to DNA sequences called hormone response elements (HREs). Binding of the receptor to DNA results in changes in gene expression of specific target genes (5).Steroid hormones were the first group of small, lipophilic molecules identified as nuclear receptor ligands. Today, the number of substances known to regulate the activity of this group of receptors is represented by a large and chemically diverse group of molecules including retinoids, vi...
Alteration of gene expression is a crucial component of adaptive responses to hypoxia. These responses are mediated by hypoxia-inducible transcription factors (HIFs). Here we describe an inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, which is a basic helix-loop-helix (bHLH)/PAS protein structurally related to HIFs. IPAS contains no endogenous transactivation function but demonstrates dominant negative regulation of HIF-mediated control of gene expression. Ectopic expression of IPAS in hepatoma cells selectively impairs induction of genes involved in adaptation to a hypoxic environment, notably the vascular endothelial growth factor (VEGF) gene, and results in retarded tumour growth and tumour vascular density in vivo. In mice, IPAS was predominantly expressed in Purkinje cells of the cerebellum and in corneal epithelium of the eye. Expression of IPAS in the cornea correlates with low levels of expression of the VEGF gene under hypoxic conditions. Application of an IPAS antisense oligonucleotide to the mouse cornea induced angiogenesis under normal oxygen conditions, and demonstrated hypoxia-dependent induction of VEGF gene expression in hypoxic corneal cells. These results indicate a previously unknown mechanism for negative regulation of angiogenesis and maintenance of an avascular phenotype.
Members of the nuclear hormone receptor gene family of transcription factors have been shown to be expressed in characteristic patterns during mouse organogenesis and postnatal development. Using an RT-PCR based screening assay, we have identified nuclear receptors expressed in embryonal carcinoma stem cells. One of the cDNAs characterized, mERR-2, was found to be expressed exclusively during a narrow developmental window in trophoblast progenitor cells between days 6.5 and 7.5 post coitum (p.c.). From 8.5 days p.c. and onwards, the mERR-2 gene activity evaded detection as analysed by in situ hybridization. We also show that the mERR-2 gene product and the estrogen receptor share a common target DNA-sequence recognition specificity unique among members of the gene family. Furthermore, efficient homodimerization and DNA-binding of the orphan receptor mERR-2 was found to be dependent on interaction with the heat shock protein 90, a molecular chaperone hitherto recognized to interact only with the steroid hormone receptor subgroup of nuclear receptors. Based on our results we suggest that the mouse orphan receptor mERR-2 has the potential to regulate overlapping gene networks with the estrogen receptor and may participate in signal transduction pathways during a short developmental period coinciding with the formation of the chorion.
We previously described a gene, Ipl (Tssc3), that is expressed selectively from the maternal allele in placenta, yolk sac, and fetal liver and that maps within the imprinted domain of mouse distal Chromosome (Chr) 7/human Chr 11p15.5 (Hum Mol Genet 6, 2021, 1997). Ipl is similar to TDAG51, a gene that is involved in FAS/CD95 expression. Here we describe another gene, Tih1 (TDAG/Ipl homologue 1), with equivalent sequence similarity to Ipl. Structural prediction indicates that the products of these three genes share a central motif resembling a pleckstrin-homology (PH) domain, and TIH1 protein has weak sequence similarity to the PH-domain protein SEC7/CYTOHESIN. Like Ipl, Tih1 is a small gene with a single small intron. Tih1 maps to distal mouse Chr 1 and human Chr 1q31, chromosomal regions that have not shown evidence for imprinting and, in contrast to Ipl, Tih1 is expressed equally from both parental alleles. Ipl, Tih1, and TDAG51 have overlapping but distinct patterns of expression. Tih1 and TDAG51 are expressed in multiple fetal and adult tissues. In contrast, during early mouse development Ipl mRNA and protein are highly specific for two tissues involved in maternal/fetal exchange: visceral endoderm of the yolk sac and labyrinthine trophoblast of the placenta. These findings highlight the dominance of chromosomal context over gene structure in some examples of parental imprinting and extend previous evidence for placenta-specific expression of imprinted genes. The data also define a new subfamily of PH domain genes.
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