Expression Of Nuclear Receptor Coactivator Research Articles

Modulation of steroid action in the central and peripheral nervous systems by nuclear receptor coactivators

Steroid hormones act in the central and peripheral nervous systems to regulate a variety of functions, including development, cell proliferation, cognition and behavior. Many of these effects of steroid hormones are mediated by their respective receptors, which are members of the nuclear receptor superfamily of transcriptional activators. A variety of cell culture studies reveal that nuclear receptor coactivators are recruited to the steroid receptor complex and are critical in modulating steroid-dependent transcription. Thus, in addition to the availability of the hormone and its receptor, the expression of nuclear receptor coactivators is essential for modulating steroid receptor-mediated transcription. This review will discuss the significance of nuclear receptor coactivators in modulating steroid-dependent gene expression in the central and peripheral nervous systems and the regulation of behavior.

Differential expression of nuclear receptor coregulators in mouse tissues

Nuclear receptor coregulators, including co-activators, co-repressors and co-activator binding proteins, play an important role in nuclear receptor activation and target gene transcription. Coregulators are diverse proteins with various functional domains, which can bind directly or indirectly to canonical nuclear receptors and form protein complexes on respective target gene responsive elements, to regulate transcription. The activation of nuclear receptor in vivo is regulated at different levels. Competition between different nuclear receptors for common limiting coregulators is one among those. For a clear understanding of the differential expression of common nuclear receptor coregulators and their role in regulation of nuclear receptor function in normal mice, we have analyzed the gene expression of nuclear receptor co-activators PBP/TRAP220, PRIP/ASC-2, CBP, SRC-1/p160, PRIC285, PRIC320 and co-activator binding proteins CARM-1 and PIMT at mRNA level by quantitative PCR (QPCR). The cDNAs for QPCR were derived from pooled tissue samples of C57BL/6J mice. Our results clearly showed differential expression of these genes in vivo, in that brain abundantly expresses SRC-1, CBP, PIMT and PRIC320 and testis expresses the most PBP. CARM-1 and PRIP were expressed more in both brain and testis. Heart and skeletal muscle expressed more CARM-1 and modest amount of PIMT, CBP and PBP. PRIC285 is highly expressed in liver, small intestine and adipose tissues. This study will help us to better understand the function of these coregulators and the complexity of nuclear receptor activation in vivo. (This work was supported by NIH)

Expression of nuclear receptor coactivators in androgen-responsive and -unresponsive motoneurons

Adult rat lumbar motoneurons in the spinal nucleus of the bulbocavernosus (SNB) respond to androgens with an increase in soma size. This response is mediated by the androgen receptor (AR) in these motoneurons. Interestingly, other lumbar motoneurons in the rat possess the AR, yet do not respond to androgens in this fashion. This paradox suggests the existence and participation of nuclear receptor coregulators in conferring direct androgen-responsiveness to select motoneurons in the adult rat spinal cord. Nuclear receptor coregulators have received much attention recently for their proposed role in enhancing or repressing the transcriptional activity of steroid hormone receptors. The present study used immunocytochemistry to identify a number of nuclear receptor coactivators that are expressed by adult lumbar motoneurons: SRC-1, SRC-2, CBP, p300, and cJUN. Results of this study indicate that all five of these coactivators are abundantly expressed in the androgen-responsive SNB, and in two adjacent motor pools, the androgen-responsive dorsolateral nucleus (DLN), and the androgen- unresponsive retrodorsolateral nucleus (RDLN). While we detected significant regional differences for only SRC-1 and cJUN, the SNB consistently contained the highest percentage of immunoreactive motoneurons for all five cofactors examined. Our results indicate five different putative cofactors have the potential to participate in motoneuronal responses to androgens, since their distribution overlaps well with the distribution of ARs in these motoneurons.

Temporal/spatial expression of nuclear receptor coactivators in the mouse lung.

Our laboratory has previously demonstrated that retinoic acid nuclear receptor, thyroid transcription factor-1 (TTF-1), and nuclear receptor coactivators such as cAMP response element binding protein (CREB) binding protein (CBP)/p300 and steroid receptor coactivator-1 (SRC-1) form an enhanceosome on the 5'-enhancer region of the human surfactant protein B gene. Immunohistochemistry was used to identify cells that coexpressed CBP/p300, SRC-1, retinoid X receptor, and TTF-1 in the developing and mature lung. CBP/p300 and SRC-1 were expressed in the adult mouse lung, CBP and p300 being present in both alveolar type I and type II epithelial cells and SRC-1 and TTF-1 being restricted to type II epithelial cells. CBP/p300, SRC-1, and TTF-1 were readily detected in the nuclei of developing respiratory epithelial tubules in fetal mice from embryonic days 10 to 18. CBP/p300 and SRC-1 were also detected in developing mesenchymal cells. These coactivators were coexpressed with TTF-1 and SP-B in human pulmonary adenocarcinoma cells (H441 cells) in vitro. Interaction assays with a two-hybrid reporter analysis demonstrated direct interactions among TTF-1, SRC-1, and CBP/p300 in H441 cells. These findings support a role for retinoic acid receptor and nuclear receptor coactivators in the regulation of SP-B gene expression in the respiratory epithelium.