Hormone-activated nuclear receptors (NRs) control myriad cellular processes. The classical paradigm for hormone delivery is secretion from endocrine organs and blood-borne distribution to responding cells. However, many hormones can also be synthesized in the same tissues in which responding cells are found (paracrine signaling). In both endocrine and paracrine signaling, numerous factors affect hormone availability to target cell NRs, including hormone access to and sequestration by carrier proteins, transport across cell membranes, metabolism, and receptor availability. These factors can differ dramatically during development, between anatomical locations, and across cell types, and may cause highly variable responses to the same hormone signal. This has been difficult to study because current approaches are unable to quantify cell-intrinsic exposure to NR hormone ligands, precluding assessment of cell-specific hormone access and signaling. We have used the ligand-dependent interaction of the endogenous glucocorticoid (GC) receptor with chromatin as a biosensor that quantifies systemic access of GCs to cells within tissues at the single cell level, showing that tissues are buffered against circulating GCs. This approach also showed highly targeted paracrine GC signaling within the thymus, where GCs promote the positive selection of thymocytes with moderate affinity for self-antigens and the development of a safe and effective T-cell repertoire. We believe that this and complementary biosensor approaches will be useful to identify endocrine and paracrine target cells in situ and quantify their exposure to hormones regardless of the mode of delivery.
In our recent publication, we show for the first time that the fungal pathogen Cryptococcus neoformans is able to manipulate host cells by producing eicosanoids that mimic those found in the host. Using complementary in vivo zebrafish and in vitro macrophage cell culture models of Cryptococcus infection, we found that these eicosanoids manipulate host innate immune cells by activating the host receptor PPAR-gamma which is an important regulator of macrophage inflammatory phenotypes. We initially identified PGE2 as the eicosanoid species responsible for this effect; however, we later found that a derivative of PGE2-15-keto-PGE2-was ultimately responsible and that this eicosanoid acted as a partial agonist to PPAR-gamma. In this commentary, we will discuss some of the concepts and conclusions in our original publication and expand on their implications and future directions.
Androgens and androgen receptor (AR, NR3C4) clearly play a crucial role in prostate cancer progression. Besides, the link between metabolic disorders and the risk of developing a prostate cancer has been emerging these last years. Interestingly, "lipid" nuclear receptors such as LXRα/NR1H3 and LXRβ/NR1H2 (as well as FXRα/NR1H4 and SHP/NR0B2) have been described to decrease the lipid metabolism, while AR increases it. Moreover, these former orphan nuclear receptors can regulate androgen levels and modulate AR activity. Thus, it is not surprising to find such receptors involved in the physiology of prostate. This review is focused on the roles of liver X receptors (LXRs), farnesoid X receptor (FXR), and small heterodimeric partner (SHP) in prostate physiology and their capabilities to interfere with the androgen-regulated pathways by modulating the levels of active androgen within the prostate. By the use of prostate cancer cell lines, mice deficient for these nuclear receptors and human tissue libraries, several authors have pointed out the putative possibility to pharmacologically target these receptors. These data open a new field of research for the development of new drugs that could overcome the castration resistance in prostate cancer, a usual phenomenon in patients.
Nuclear hormone receptors (NRs) are evolutionarily conserved ligand-dependent transcription factors. They are essential for human life, mediating the actions of lipophilic molecules, such as steroid hormones and metabolites of fatty acid, cholesterol, and external toxic compounds. The C2H2-type zinc finger proteins (ZNFs) form the largest family of the transcription factors in humans and are characterized by multiple, tandemly arranged zinc fingers. Many of the C2H2-type ZNFs are conserved throughout evolution, suggesting their involvement in preserved biological activities, such as general transcriptional regulation and development/differentiation of organs/tissues observed in the early embryonic phase. However, some C2H2-type ZNFs, such as those with the Krüppel-associated box (KRAB) domain, appeared relatively late in evolution and have significantly increased family members in mammals including humans, possibly modulating their complicated transcriptional network and/or supporting the morphological development/functions specific to them. Such evolutional characteristics of the C2H2-type ZNFs indicate that these molecules influence the NR functions conserved through evolution, whereas some also adjust them to meet with specific needs of higher organisms. We review the interaction between NRs and C2H2-type ZNFs by focusing on some of the latter molecules.
The N-terminal domain (NTD) of nuclear receptor superfamily members has been recently reported to regulate functions of the receptor through the interaction between the NTD and the C-terminal ligand binding domain (LBD), so-called an N/C interaction. Although this N/C interaction has been demonstrated in various nuclear receptors, eg, androgen receptor, this concept has not been observed in glucocorticoid receptor (GR). We hypothesized that GR requires its co-chaperone CCRP (cytoplasmic constitutive active/androstane receptor retention protein) to form a stable N/C interaction. This hypothesis was examined by co-immunoprecipitation assays using GR fragments overexpressing COS-1 cell lysate. Here, we demonstrated that GR undergoes the N/C interaction between the 26VMDFY30 motif in the NTD and the LBD. More importantly, co-chaperone CCRP is now found to induce this interaction. By the fact that a negative charge at Y30 disrupts this interaction, this residue, a potential phosphorylation site, was indicated to regulate the GR N/C interaction critically. Utilizing Y30F and Y30E mutants as N/C interacting and noninteracting forms of GR, respectively, a 2-dimensional blue native/sodium dodecyl sulfate-polyacrylamide gel electrophoresis was performed to examine whether or not the N/C interaction regulated formation of GR complexes. A cDNA microarray analysis was performed with COS-1 cells expressing Y30F or Y30E. We will present experimental data to demonstrate that CCRP is essential for GR to form the N/C interaction and will discuss its implications in GR functions.
