SRC-1 Deficiency Increases Susceptibility of Mice to Depressive-Like Behavior After Exposure to CUMS

Neurochemical Research - Steroid receptor coactivator 1 (SRC-1) is one of the coactivators recruited by the nuclear receptors (NRs) when NRs are activated by steroid hormones, such as...     

Nuclear receptor expression links the circadian clock to metabolism

As sensors for fat-soluble hormones and dietary lipids, oscillations in nuclear receptor (NR) expression in key metabolic tissues may contribute to circadian entrainment of nutrient and energy metabolism. Surveying the diurnal expression profiles of all 49 mouse nuclear receptors in white and brown adipose tissue, liver, and skeletal muscle revealed that of the 45 NRs expressed, 25 are in a rhythmic cycle and 3 exhibit a single transient pulse of expression 4 hr into the light cycle. While thyroid hormones are generally constant, we find that TRalpha and beta dramatically cycle, suggesting that fundamental concepts such as "basal metabolism" may require reexamination. The dynamic but coordinated changes in nuclear receptor expression, along with their key target genes, offers a logical explanation for known cyclic behavior of lipid and glucose metabolism and suggests novel roles for endocrine and orphan receptors in coupling the peripheral circadian clock to divergent metabolic outputs.     

Minireview: nuclear receptors and breast cancer

Until recently, the study of nuclear receptor (NR) function in breast cancer biology has been largely limited to estrogen and progesterone receptors. The development of reliable gene expression arrays, real-time quantitative RT-PCR, and immunohistochemical techniques for studying NR superfamily members in primary human breast cancers has now revealed the presence and potential importance of several additional NRs in the biology of breast cancer. These include receptors for steroid hormones (including androgens and corticosteroids), fat-soluble vitamins A and D, fatty acids, and xenobiotic lipids derived from diet. It is now clear that after NR activation, both genomic and nongenomic NR pathways can coordinately activate growth factor signaling pathways. Advances in our understanding of both NR functional networks and epithelial cell growth factor signaling pathways have revealed a frequent interplay between NR and epithelial cell growth factor family signaling that is clinically relevant to breast cancer. Understanding how growth factor receptors and their downstream kinases are activated by NRs (and vice-versa) is a central goal for maximizing treatment opportunities in breast cancer. In addition to the estrogen receptor, it is predicted that modulating the activity of other NRs will soon provide novel prevention and treatment approaches for breast cancer patients.     

Molecular characterisation of a serum-responsive, DAF-12-like nuclear hormone receptor of the fox-tapeworm Echinococcus multilocularis

As the primary mediators of lipophilic and steroid hormone signalling, the family of nuclear receptors (NRs) plays a central role in the regulation of metazoan development. Lipophilic hormones are also thought to be important players in the molecular interaction between larval cestodes and their hosts but no member of the NR family has yet been characterised in this group of parasites. In this work, we provide for the first time evidence for the presence of NRs in cestodes of the genus Echinococcus. By bioinformatic analyses, we identified a set of 17 NRs in the genomes of E. multilocularis and E. granulosus which broadly overlapped with the set of NRs that is expressed by schistosomes, but also contained several members that are unique to cestodes. One of these receptors, EmNHR1, displayed structural homologies to the DAF-12/HR-96 subfamily of NRs that regulates cholesterol homeostasis and longevity in metazoans. By RT-PCR analyses, we demonstrate that the EmNHR1 encoding gene is expressed in all Echinococcus larval stages that are involved in the infection of the intermediate host. By yeast two-hybrid analyses, we further demonstrate cross-communication between EmNHR1 and TGF-β signalling pathways in Echinococcus and that mammalian serum contains a ligand that induces homodimerisation of the EmNHR1 ligand-binding domain. EmNHR1 could thus play an important role in hormonal host-parasite cross-communication mechanisms during an infection. On the basis of our results, further investigations into the role of NR signalling in cestode development and host-parasite interaction will be greatly facilitated.     

Steroid hormone biotransformation and xenobiotic induction of hepatic steroid metabolizing enzymes

Normal reproductive development depends on the interplay of steroid hormones with their receptors at specific tissue sites. The concentrations of hormone ligands in the circulation and at target sites are maintained through coordinated regulation on steroid biosynthesis and degradation. Changed bioavailability of steroids, through alteration of steroidogenesis or biotransformation rates, leads to changes in endocrine function. Steroid hormones lose their receptor reactivity in most cases when they are bound to binding proteins, while metabolic conversion can result in either active or inactive metabolites. Hydroxylation by cytochrome P450 (CYP) enzymes and conjugation with glucuronide and sulfate are among the major hepatic pathways of steroid inactivation. The expression of these biotransformation enzymes can be induced by many xenobiotics. The barbiturate phenobarbital and the environmental toxicant 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) are among the well characterized inducers for the CYP 2B and 3A enzymes and selected conjugation enzymes. The induction of the steroid biotransformation enzymes is partly mediated through the activation of a group of nuclear receptors including the glucocorticoid receptor, the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the peroxisome proliferator activated receptors (PPAR). Drug or chemical-induced increases in hepatic enzyme activities are often a basis for drug-drug interactions that lead to enhanced elimination and reduced therapeutic efficacy of steroidal drugs. The effects of enzyme induction on endogenous steroid clearance, along with its possible consequence, are less well understood. While enzyme induction by xenobiotics may increase clearance of the endogenous steroid, regulatory mechanisms for steroid homeostasis may adapt and compensate for altered clearance.     

Negative regulation of parathyroid hormone-related protein expression by steroid hormones

Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here we studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor α, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.