| Popis: |
Although a connection between breast cancer and the ovary was made by Sir George Beatson in 1896 and estrogen was purified in 1920, it remained puzzling as to how the hormone exerted its biological effects. In the late 1950s, when Elwood Jensen delved into this problem by asking, essentially, “What does tissue do with this hormone?” little did he know that his quest would lead to the establishment of the nuclear receptor field. The late 1950s was the era of intermediary metabolism and enzymology, when steroid hormones were considered likely substrates in the formation of metabolites that functioned as cofactors in an essential metabolic pathway. The biological responses to estrogens and other steroids were thought to be mediated by enzymes. Against this background and prevailing dogma, Jensen and colleagues defined the biochemical mechanisms by which steroid hormones exert their effects. While working at the University of Chicago's Ben May Institute for Cancer Research, they synthesized tritium-labeled estradiol and concurrently developed a new method to measure its uptake in biological material. These tools enabled them to determine the biochemical fate of physiological amounts of hormone. They discovered that the reproductive tissues of the immature rat contain characteristic hormone-binding components with which estradiol reacts to induce uterine growth without itself being chemically changed. From the close correlation between the inhibition of binding and inhibition of growth response, Jensen established that the binding substances were receptors. Thus, we saw the birth of the first member of the nuclear receptor family (known as the estrogen receptor). These findings stimulated the search for other physiological receptors, and the pioneering works by Pierre Chambon, Ronald Evans, Jan-Åke Gustafsson, Bert W. O'Malley, and Keith Yamamoto led to the discoveries of the glucocorticoid receptor (GR),2 progesterone receptor, retinoic acid receptor, and orphan receptors. In a rather short span of time, the nuclear receptor family has grown into a 49-member-strong “superfamily.” This is a family whose members, functioning as sequence-specific transcription factors, have defined the many intricacies of the mechanism of transcription. These ligand-dependent transcription factors generally possess similar “domain organizations,” of which the DNA-binding domain and the ligand-binding domain are critical in amplifying the hormonal signals via the receptor target genes. The nuclear receptor family is divided into four groups: (i) Group 1 is composed of steroid hormone receptors that control target gene transcription by binding as homodimers to response element (RE) palindromes; (ii) in Group 2, the nuclear receptors heterodimerize with retinoid X receptor and generally bind to direct repeat REs; (iii) Group 3 consists of those orphan receptors that function as homodimers and bind to direct repeat REs; and (iv) orphan receptors in Group 4 function as monomers and bind to single REs. Since the early demonstration by Jack Gorski and Jensen that the estrogen receptor (ER) activates transcription, the nuclear receptor field has come a long way. In addition to the first cloning of the polymerase II transcription factors (GR and ER cDNAs), of note is the discovery of steroid receptor coactivators (SRCs), a truly major piece of the transcriptional jigsaw puzzle, described by the laboratories of O'Malley and Myles Brown. The induction of coactivators and corepressors in the transcriptional machinery has expanded tremendously our understanding of this complex process. We now know that ligand binding to the respective receptors triggers a fascinating chain of events, including the translocation of the receptors to the nucleus, ligand-induced changes in the receptor conformations, receptor dimerization, interaction with the target gene promoter elements, recruitment of coactivators (or corepressors), chromatin remodeling, and subsequent interaction with the polymerase II complex to initiate transcription. By virtue of their abilities to regulate a myriad of human developmental and physiological functions (reproduction, development, metabolism), nuclear receptors have been implicated in a wide range of diseases, such as cancer, diabetes, obesity, etc. Not surprisingly, drug companies are spending billions of dollars to develop medicines for cancer and metabolic disorders that involve nuclear receptors. More than 50 years after the discovery of the ER, the scientific community owes Jensen and other founding members of the nuclear receptor family much gratitude, for they have taken us through a remarkable expedition filled with eureka moments to understand how hormones and other ligands function! This thematic minireview series will cover a range of topics in the nuclear receptor field. The minireviews include the current studies of identifying subtypes of the GR. Different receptors arise from alternative mRNA splicing and from the use of different promoter start sites and post-translational modifications, such as phosphorylation. The series covers the physiological roles of the different GRs. The field of orphan nuclear receptors and the search for possible ligands also are reviewed. One minireview concentrates largely on the following nuclear receptors: peroxisome proliferator-activated receptor (PPAR) α, PPARγ, Rev-erbα, and retinoic acid receptor-related orphan receptor α. ERα was the first identified and has been studied the most, whereas ERβ has not been studied in the same detail. ERβ is very important, and one of the minireviews provides a summary of the new biological functions that are being ascribed to it. Also, the development of small molecule inhibitors for the ER will be considered. An important aspect of nuclear receptor function is how these receptors function in transcription. The role of transcriptional coactivators in nuclear receptor gene regulation will be reviewed as well as how signal amplification and interaction are involved in transcription regulation by steroids. The SRC/p160 family of coregulators includes SRC-1, SRC-2, and SRC-3, and the latter has been shown to act as an oncogene, particularly in breast cancer. Molecular analysis of its role in breast cancer progression and metastasis will be the focus of one of the minireviews. In addition, interactions of nuclear receptors with the genome will be reviewed, as will the role of the homeodomain protein HoxB13 in specifying the cellular response to androgens. Mining nuclear receptor cistromes and how nuclear receptors reset metabolism also will be considered. The association of nuclear receptors (e.g. PPARδ) with physiological functions, such as circadian rhythm and muscle functions, will also be addressed. Finally, the role of nuclear receptors in disease using the retinoid X receptor α/β knock-out and transgenic mouse model skin syndromes and asthma will be reviewed. These are diverse and important topics that are critical in understanding the regulation of nuclear receptors and the biological roles they play in normal function and disease. |
