Nuclear receptor signaling最新文献

The last few years have witnessed a rapid increase in our knowledge of the retinoid-related orphan receptors RORalpha, -beta, and -gamma (NR1F1-3), their mechanism of action, physiological functions, and their potential role in several pathologies. The characterization of ROR-deficient mice and gene expression profiling in particular have provided great insights into the critical functions of RORs in the regulation of a variety of physiological processes. These studies revealed that RORalpha plays a critical role in the development of the cerebellum, that both RORalpha and RORbeta are required for the maturation of photoreceptors in the retina, and that RORgamma is essential for the development of several secondary lymphoid tissues, including lymph nodes. RORs have been further implicated in the regulation of various metabolic pathways, energy homeostasis, and thymopoiesis. Recent studies identified a critical role for RORgamma in lineage specification of uncommitted CD4+ T helper cells into Th17 cells. In addition, RORs regulate the expression of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expression of downstream (metabolic) genes. Study of ROR target genes has provided insights into the mechanisms by which RORs control these processes. Moreover, several reports have presented evidence for a potential role of RORs in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, and obesity, and raised the possibility that RORs may serve as potential targets for chemotherapeutic intervention. This prospect was strengthened by recent evidence showing that RORs can function as ligand-dependent transcription factors.

Androgens control male sexual development and maintenance of the adult male phenotype. They have very divergent effects on their target organs like the reproductive organs, muscle, bone, brain and skin. This is explained in part by the fact that different cell types respond differently to androgen stimulus, even when all these responses are mediated by the same intracellular androgen receptor. To understand these tissue- and cell-specific readouts of androgens, we have to learn the many different steps in the transcription activation mechanisms of the androgen receptor (NR3C4). Like all nuclear receptors, the steroid receptors have a central DNA-binding domain connected to a ligand-binding domain by a hinge region. In addition, all steroid receptors have a relatively large amino-terminal domain. Despite the overall structural homology with other nuclear receptors, the androgen receptor has several specific characteristics which will be discussed here. This receptor can bind two types of androgen response elements (AREs): one type being similar to the classical GRE/PRE-type elements, the other type being the more divergent and more selective AREs. The hormone-binding domain has low intrinsic transactivation properties, a feature that correlates with the low affinity of this domain for the canonical LxxLL-bearing coactivators. For the androgen receptor, transcriptional activation involves the alternative recruitment of coactivators to different regions in the amino-terminal domain, as well as the hinge region. Finally, a very strong ligand-induced interaction between the amino-terminal domain and the ligand-binding domain of the androgen receptor seems to be involved in many aspects of its function as a transcription factor. This review describes the current knowledge on the structure-function relationships within the domains of the androgen receptor and tries to integrate the involvement of different domains, subdomains and motifs in the functioning of this receptor as a transcription factor with tissue- and cell-specific readouts.

Steroid hormone receptors (SHR) belong to a large family of ligand-activated transcription factors that perform their biological functions by enhancing the transcription of specific target genes. The transactivation functions of SHRs are regulated by a specialized group of proteins called coactivators. The SHR coactivators represent a growing class of proteins with various enzymatic activities that serve to modify the chromatin to facilitate the transcription of SHR target genes. The ubiquitin-proteasome pathway enzymes have also been added to the growing list of enzymatic activities that are recruited to the SHR target gene promoters during transcription. One such ubiquitin-proteasome pathway enzyme to be identified and characterized as a SHR coactivator was E6-associated protein (E6-AP). E6-AP is a hect (homologous to E6-associated protein carboxy-terminal domain) domain containing E3 ubiquitin ligase that possesses two independent separable functions; a coactivation function and an ubiquitin-protein ligase activity. Being a component of the ubiquitin-proteasome pathway, it is postulated that E6-AP may orchestrate the dynamics of steroid hormone receptor-mediated transcription by regulating the degradation of the transcriptional complexes. E6-AP has also been shown to be involved in the regulation of various aspects of reproduction such as prostate and mammary gland development. Furthermore, it has been demonstrated that E6-AP expression is down-regulated in breast and prostate tumors and that the expression of E6-AP is inversely associated with that of estrogen and androgen receptors. This review summarizes our current knowledge about the structures, molecular mechanisms, spatiotemporal expression patterns and biological functions of E6-AP.

The way in which estrogen receptor alpha (ERalpha) mediates gene transcription and hormone-dependent cancer cell proliferation is now being largely reconsidered in view of several recent discoveries. ERalpha-mediated transcription appears to be a cyclic and transient process where the proteasome - and thus receptor degradation - plays a pivotal role. In view of our recent investigations, which demonstrate the estrogenic activity of a synthetic peptide corresponding to a regulatory motif of the receptor (ERalpha17p), we propose that ERalpha proteasomal degradation could induce the emergence of regulatory peptide(s). The latter would function as a signal and contribute to the ERalpha activation process, amplifying the initial hormonal stimulation and giving rise to sustained estrogenic response.

Recent genomic analyses of transcription factor binding, histone modification, and gene expression have provided a global view of transcriptional regulation by nuclear receptors (NRs) that complements an existing large body of literature on gene-specific studies. The picture emerging from these genomic studies indicates that NRs bind at promoter-proximal and promoter-distal enhancers in conjunction with other transcription factors (e.g., activator protein-1, Sp1 and FOXA1). This binding promotes the recruitment of coregulators that mediate the posttranslational modification of histones at promoters and enhancers. Ultimately, signaling through liganded NRs stimulates changes in the occupancy of RNA polymerase II (Pol II) or the activation of preloaded Pol II at target promoters. Chromosomal looping and/or Pol II tracking may underlie promoter-enhancer communication. Interestingly, the direct target genes of NR signaling represent a limited subset of all the genes regulated by NR ligands, with the rest being regulated through secondary effects. As suggested by previous gene-specific analyses, NR-mediated outcomes are highly cell type- and promoter-specific, highlighting the complexity of transcriptional regulation by NRs and the value of genomic analyses for identifying commonly shared patterns. Overall, NRs share common themes in their patterns of localization and transcriptional regulation across mammalian genomes. In this review, we provide an overview of recent advances in the understanding of NR-mediated transcription garnered from genomic analyses of gene expression, factor localization, and target DNA sequences.

The discovery of a second estrogen receptor (ER), designated ERbeta (NR3A2), has redefined our knowledge about the mechanisms underlying cellular signaling by estrogens and has broad implications for our understanding of regulation of estrogen-responsive tissues. Highly variable and even contrasting effects of estrogens in different tissues seem to be at least partially explained by different estrogen signaling pathways, involving ERalpha (NR3A1) and/or ERbeta. To date, two key conclusions can be drawn from the significant body of work carried out on the specific roles of the two receptor subtypes in diverse estrogen target tissues. First, ERalpha and ERbeta have different biological functions, as indicated by their specific expression patterns and the distinct phenotypes observed in ERalpha and ERbeta knockout (alphaERKO and betaERKO) mice. Second, ERalpha and ERbeta appear to have overlapping but also unique sets of downstream target genes, as judged from a set of microarray experiments. Thus, ERalpha and ERbeta have different transcriptional activities in certain ligand, cell-type, and promoter contexts, which may help to explain some of the major differences in their tissue-specific biological actions. The phenotypes observed for betaERKO mice have suggested certain therapeutic areas to be further explored. The development of ERbeta-selective ligands active in animal disease models indicates new avenues for clinical exploration. ERbeta agonists are being explored and validated as drugs for a growing number of indications. Hopefully, some ERbeta targeted drugs will prove to be efficient in enhancing human health.

NCoA6 (also referred to as NRC, ASC-2, TRBP, PRIP and RAP250) was originally isolated as a ligand-dependent nuclear receptor interacting protein. However, NCoA6 is a multifunctional coregulator or coactivator necessary for transcriptional activation of a wide spectrum of target genes. The NCoA6 gene is amplified and overexpressed in breast, colon and lung cancers. NCoA6 is a 250 kDa protein which harbors a potent N-terminal activation domain, AD1; and a second, centrally-located activation domain, AD2, which is necessary for nuclear receptor signaling. The intrinsic activation potential of NCoA6 is regulated by its C-terminal STL regulatory domain. Near AD2 is an LxxLL-1 motif which interacts with a wide spectrum of ligand-bound NRs with high-affinity. A second LxxLL motif (LxxLL-2) located towards the C-terminal region is more restricted in its NR specificity. The potential role of NCoA6 as a co-integrator is suggested by its ability to enhance transcriptional activation of a wide variety of transcription factors and from its in vivo association with a number of known cofactors including CBP/p300. NCoA6 has been shown to associate with at least three distinct coactivator complexes containing Set methyltransferases as core polypeptides. The composition of these complexes suggests that NCoA6 may play a fundamental role in transcriptional activation by modulating chromatin structure through histone methylation. Knockout studies in mice suggest that NCoA6 is an essential coactivator. NCoA6-/- embryos die between 8.5-12.5 dpc from general growth retardation coupled with developmental defects in the heart, liver, brain and placenta. NCoA6-/- MEFs grow at a reduced rate compared to WT MEFs and spontaneously undergo apoptosis, indicating the importance of NCoA6 as a prosurvival and anti-apoptotic gene. Studies with NCoA6+/- and conditional knockout mice suggest that NCoA6 is a pleiotropic coregulator involved in growth, development, wound healing and maintenance of energy homeostasis.

The packaging of genomic DNA into chromatin, often viewed as an impediment to the transcription process, plays a fundamental role in the regulation of gene expression. Chromatin remodeling proteins have been shown to alter local chromatin structure and facilitate recruitment of essential factors required for transcription. Brahma-related gene-1 (BRG1), the central catalytic subunit of numerous chromatin-modifying enzymatic complexes, uses the energy derived from ATP-hydrolysis to disrupt the chromatin architecture of target promoters. In this review, we examine BRG1 as a major coregulator of transcription. BRG1 has been implicated in the activation and repression of gene expression through the modulation of chromatin in various tissues and physiological conditions. Outstanding examples are studies demonstrating that BRG1 is a necessary component for nuclear receptor-mediated transcriptional activation. The remodeling protein is also associated with transcriptional corepressor complexes which recruit remodeling activity to target promoters for gene silencing. Taken together, BRG1 appears to be a critical modulator of transcriptional regulation in cellular processes including transcriptional regulation, replication, DNA repair and recombination.

The androgen receptor (AR) is a critical effector of prostate cancer development and progression. The dependence of this tumor type on AR activity is exploited in treatment of disseminated prostate cancers, wherein ablation of AR function (achieved either through ligand depletion and/or the use of AR antagonists) is the first line of therapeutic intervention. These strategies are initially effective, and induce a mixed response of cell cycle arrest or apoptosis in prostate cancer cells. However, recurrent, incurable tumors ultimately arise as a result of inappropriately restored AR function. Based on these observations, it is imperative to define the mechanisms by which AR controls cancer cell proliferation. Mechanistic investigation has revealed that AR acts as a master regulator of G1-S phase progression, able to induce signals that promote G1 cyclin-dependent kinase (CDK) activity, induce phosphorylation/inactivation of the retinoblastoma tumor suppressor (RB), and thereby govern androgen-dependent proliferation. These functions appear to be independent of the recently identified TMPRSS2-ETS fusions. Once engaged, several components of the cell cycle machinery actively modulate AR activity throughout the cell cycle, thus indicating that crosstalk between the AR and cell cycle pathways likely modulate the mitogenic response to androgen. As will be discussed, discrete aberrations in this process can alter the proliferative response to androgen, and potentially subvert hormonal control of tumor progression.

The normal development and physiological functions of multicellular organisms are regulated by complex gene transcriptional networks that include myriad transcription factors, their associating coregulators, and multiple chromatin-modifying factors. Aberrant gene transcriptional regulation resulting from mutations among these elements often leads to developmental defects and diseases. This review article concentrates on the Atrophin family proteins, including vertebrate Atrophin-1 (ATN1), vertebrate arginine-glutamic acid dipeptide repeats protein (RERE), and Drosophila Atrophin (Atro), which we recently identified as nuclear receptor corepressors. Disruption of Atrophin-mediated pathways causes multiple developmental defects in mouse, zebrafish, and Drosophila, while an aberrant form of ATN1 and altered expression levels of RERE are associated with neurodegenerative disease and cancer in humans, respectively. We here provide an overview of current knowledge about these Atrophin proteins. We hope that this information on Atrophin proteins may help stimulate fresh ideas about how this newly identified class of nuclear receptor corepressors aids specific nuclear receptors and other transcriptional factors in regulating gene transcription, manifesting physiological effects, and causing diseases.