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COUP-TF-like receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7, 2]) have yet to be officially paired with an endogenous ligand.

Supplementary Video 2 from Steroid Receptor Coactivator-3/AIB1 Promotes Cell Migration and Invasiveness through Focal Adhesion Turnover and Matrix Metalloproteinase Expression

Supplementary Data Legend from Deregulated CDC25A Expression Promotes Mammary Tumorigenesis with Genomic Instability

Supplementary Figure 1 from Steroid Receptor Coactivator-3/AIB1 Promotes Cell Migration and Invasiveness through Focal Adhesion Turnover and Matrix Metalloproteinase Expression

The significance of angiogenesis in cancer biology and therapy is well established. In this study, we used the prototypical RIP-Tag model of multistage pancreatic islet tumorigenesis to show that the nuclear receptor COUP-TFII is essential to regulate the balance between pro- and anti-angiogenic molecules that influence the angiogenic switch in cancer. Conditional ablation of COUP-TFII in the tumor microenvironment severely compromised neoangiogenesis and lymphangiogenesis during pancreatic tumor progression and metastasis. We found that COUP-TFII plays a cell-autonomous role in endothelial cells to control blood vessel sprouting by regulating cell proliferation and migration. Mechanistic investigations revealed that COUP-TFII suppressed vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2) signaling by transcriptionally repressing the expression of VEGFR-1, thereby curtailing a central angiogenic driver of vascular growth. Taken together, our results implicate COUP-TFII as a critical factor in tumor angiogenesis through regulation of VEGF/VEGFR-2 signaling, suggesting COUP-TFII as a candidate target for antiangiogenic therapy. Cancer Res; 70(21); 8812–21. ©2010 AACR.

Supplementary Data I from Deregulated CDC25A Expression Promotes Mammary Tumorigenesis with Genomic Instability

Supplementary Figure 6 from Steroid Receptor Coactivator-3/AIB1 Promotes Cell Migration and Invasiveness through Focal Adhesion Turnover and Matrix Metalloproteinase Expression

Supplementary Figure 5 from Steroid Receptor Coactivator-3/AIB1 Promotes Cell Migration and Invasiveness through Focal Adhesion Turnover and Matrix Metalloproteinase Expression

Supplementary Figure 2 from Steroid Receptor Coactivator-3/AIB1 Promotes Cell Migration and Invasiveness through Focal Adhesion Turnover and Matrix Metalloproteinase Expression

Checkpoint pathways help cells maintain genomic integrity, delaying cell cycle progression in response to various risks of fidelity, such as genotoxic stresses, compromised DNA replication, and impaired spindle control. Cancer cells frequently exhibit genomic instability, and recent studies showed that checkpoint pathways are likely to serve as a tumor-suppressive barrier in vivo. The cell cycle–promoting phosphatase CDC25A is an activator of cyclin-dependent kinases and one of the downstream targets for the CHK1-mediated checkpoint pathway. Whereas CDC25A overexpression is observed in various human cancer tissues, it has not been determined whether deregulated CDC25A expression triggers or promotes tumorigenesis in vivo. Here, we show that transgenic expression of CDC25A cooperates markedly with oncogenic ras or neu in murine mammary tumorigenesis. MMTV-CDC25A transgenic mice exhibit alveolar hyperplasia in the mammary tissue but do not develop spontaneous mammary tumors. The MMTV-CDC25A transgene markedly shortens latency of tumorigenesis in MMTV-ras mice. The MMTV-CDC25A transgene also accelerates tumor growth in MMTV-neu mice with apparent cell cycle miscoordination. CDC25A-overexpressing tumors, which invade more aggressively, exhibit various chromosomal aberrations on fragile regions, including the mouse counterpart of human 1p31-36, according to array-based comparative genomic hybridization and karyotyping. The chromosomal aberrations account for substantial changes in gene expression profile rendered by transgenic expression of CDC25A, including down-regulation of Trp73. These data indicate that deregulated control of cellular CDC25A levels leads to in vivo genomic instability, which cooperates with the neu-ras oncogenic pathway in mammary tumorigenesis. [Cancer Res 2007;67(3):984–91]

Supplementary Video 1 from Steroid Receptor Coactivator-3/AIB1 Promotes Cell Migration and Invasiveness through Focal Adhesion Turnover and Matrix Metalloproteinase Expression

Supplementary Figure 3 from Steroid Receptor Coactivator-3/AIB1 Promotes Cell Migration and Invasiveness through Focal Adhesion Turnover and Matrix Metalloproteinase Expression

Methods and Materials from Dual Roles for Coactivator Activator and its Counterbalancing Isoform Coactivator Modulator in Human Kidney Cell Tumorigenesis

Supplementary Figure 1 from Dual Roles for Coactivator Activator and its Counterbalancing Isoform Coactivator Modulator in Human Kidney Cell Tumorigenesis

Supplementary Figure 4 from Steroid Receptor Coactivator-3/AIB1 Promotes Cell Migration and Invasiveness through Focal Adhesion Turnover and Matrix Metalloproteinase Expression

Supplementary Methods, Figures 1-5 from Nuclear Receptor COUP-TFII Controls Pancreatic Islet Tumor Angiogenesis by Regulating Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor-2 Signaling

Supplementary Methods, Legends for Figures and Videos from Steroid Receptor Coactivator-3/AIB1 Promotes Cell Migration and Invasiveness through Focal Adhesion Turnover and Matrix Metalloproteinase Expression

Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also revealed that JQ1 can activate additional oncogenic pathways and may affect epithelial-to-mesenchymal transition (EMT). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein–independent manner. Multiple invasion pathways including EMT, bone morphogenetic protein (BMP) signaling, chemokine signaling, and focal adhesion were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of Forkhead box protein A1 (FOXA1), an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1 and inactivated FOXA1 binding to its interacting repressors TLE3, HDAC7, and NFIC, thereby blocking FOXA1-repressive function and activating the invasion genes. Our findings indicate that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents cannot be ignored during cancer treatment, especially in FOXA1-related cancers.

We identified inhibitors targeting COUP-TFII for the treatment of diseases including prostate cancer., The orphan nuclear receptor COUP-TFII is expressed at a low level in adult tissues, but its expression is increased and shown to promote progression of multiple diseases, including prostate cancer, heart failure, and muscular dystrophy. Suppression of COUP-TFII slows disease progression, making it an intriguing therapeutic target. Here, we identified a potent and specific COUP-TFII inhibitor through high-throughput screening. The inhibitor specifically suppressed COUP-TFII activity to regulate its target genes. Mechanistically, the inhibitor directly bound to the COUP-TFII ligand-binding domain and disrupted COUP-TFII interaction with transcription regulators, including FOXA1, thus repressing COUP-TFII activity on target gene regulation. Through blocking COUP-TFII’s oncogenic activity in prostate cancer, the inhibitor efficiently exerted a potent antitumor effect in xenograft mouse models and patient-derived xenograft models. Our study identified a potent and specific COUP-TFII inhibitor that may be useful for the treatment of prostate cancer and possibly other diseases.

Altered re-wiring of cell metabolism and transcriptional programs are both hallmarks of cancer that sustain rapid proliferation and metastasis1. However mechanisms controlling the interplay between metabolic reprogramming and transcriptional regulation remain elusive. Here we show that metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) regulates transcriptional reprogramming by activating the oncogenic steroid receptor coactivator-3 (SRC-3). We employed a method for identifying potential kinases that modulate coactivator functions by integrating kinome-wide RNA interference (RNAi)-based screening coupled to intrinsic SRC-3-transcriptional response. PFKFB4, a regulatory enzyme that synthesizes an allosteric stimulator of glycolysis2, was found to be a robust stimulator of SRC-3 that co-activates estrogen receptor (ER). PFKFB4 phosphorylates SRC-3 at serine 857 (S857) enhancing its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient SRC-3 mutant S857A (SRC-3S857A) significantly abolishes SRC-3-mediated transcriptional output. Functionally, PFKFB4-driven SRC-3 activation drives glucose flux towards the pentose phosphate pathway enabling purine synthesis by transcriptionally upregulating the expression of enzyme transketolase (TKT). In addition, two enzymes adenosine monophosphate deaminase-1 (AMPD1) and xanthine dehydrogenase (XDH) involved in purine metabolism were identified as SRC-3 targets which may or may not be directly involved in purine synthesis. Mechanistically, phosphorylation at S857 increases coactivator interaction with the transcription factor ATF4 stabilizing SRC-3/ATF4 recruitment to target gene promoters. Ablation of SRC-3 or PFKFB4 suppresses in vivo breast tumor growth and prevents metastasis to the lung from an orthotopic setting as does an SRC-3S857A mutant. PFKFB4 and pSRC-3-S857 levels are elevated and significantly correlate in ER positive tumors whereas, in patients with basal subtype, PFKFB4-SRC-3 drives a common protein signature that positively correlates with the poor survival of breast cancer patients. These findings suggest that the Warburg-pathway enzyme PFKFB4 acts as a molecular fulcrum coupling sugar metabolism to transcriptional activation by stimulating SRC-3 critical to promote aggressive metastatic tumors.

The precise timing of progesterone signaling through its cognate receptor, the progesterone receptor (PGR), is critical for the establishment and maintenance of pregnancy. Loss of PGR expression in the murine uterine epithelium during the preimplantation period is a marker for uterine receptivity and embryo attachment. We hypothesized that the decrease in progesterone receptor A (PGRA) expression is necessary for successful embryo implantation. To test this hypothesis, a mouse model constitutively expressing PGRA (mPgrALsL/+) was generated. Expression of PGRA in all uterine compartments (Pgrcre) or uterine epithelium (Wnt7acre) resulted in infertility with defects in embryo attachment and stromal decidualization. Expression of critical PGRA target genes, indian hedgehog, and amphiregulin (Areg), was maintained through the window of receptivity while the estrogen receptor target gene, the leukemia inhibitory factor (Lif), a key regulator of embryo receptivity, was decreased. Transcriptomic and cistromic analyses of the mouse uterus at day 4.5 of pregnancy identified an altered group of genes regulating molecular transport in the control of fluid and ion levels within the uterine interstitial space. Additionally, LIF and its cognate receptor, the leukemia inhibitory factor receptor (LIFR), exhibited PGR-binding events in regions upstream of the transcriptional start sites, suggesting PGRA is inhibiting transcription at these loci. Therefore, downregulation of the PGRA isoform at the window of receptivity is necessary for the attenuation of hedgehog signaling, transcriptional activation of LIF signaling, and modulation of solutes and fluid, producing a receptive environment for the attaching embryo.

Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. The role of BRD4 in cancer has been attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and endogenous protein detection, along with transgene expression, the less abundant BRD4 short isoform (BRD4-S) is oncogenic while BRD4-L is tumor-suppressive in breast cancer cell proliferation and migration, as well as mammary tumor formation and metastasis. Through integrated RNA-seq, genome-wide ChIP-seq, and CUT&RUN association profiling, we identify the Engrailed-1 (EN1) homeobox transcription factor as a key BRD4-S coregulator, particularly in triple-negative breast cancer. BRD4-S and EN1 comodulate the extracellular matrix (ECM)-associated matrisome network, including type II cystatin gene cluster, mucin 5, and cathepsin loci, via enhancer regulation of cancer-associated genes and pathways. Our work highlights the importance of targeted therapies for the oncogenic, but not tumor-suppressive, activity of BRD4.

We report a novel pathway where FANCD2 binds to nuclear receptors, COUP-TFII/TR4, to promote alternative lengthening of telomeres., Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle-wasting disease caused by mutations in the dystrophin gene. Although dystrophin deficiency in myofiber triggers the disease’s pathological changes, the degree of satellite cell (SC) dysfunction defines disease progression. Here, we have identified chicken ovalbumin upstream promoter–transcription factor II (COUP-TFII) hyperactivity as a contributing factor underlying muscular dystrophy in a dystrophin-deficient murine model of DMD. Ectopic expression of COUP-TFII in murine SCs led to Duchenne-like dystrophy in the muscles of control animals and exacerbated degenerative myopathies in dystrophin-deficient mice. COUP-TFII–overexpressing mice exhibited regenerative failure that was attributed to deficient SC proliferation and myoblast fusion. Mechanistically, we determined that COUP-TFII coordinated a regenerative program through combined regulation of multiple promyogenic factors. Furthermore, inhibition of COUP-TFII preserved SC function and counteracted the muscle weakness associated with Duchenne-like dystrophy in the murine model, suggesting that targeting COUP-TFII is a potential treatment for DMD. Together, our findings reveal a regulatory role of COUP-TFII in the development of muscular dystrophy and open up a potential therapeutic opportunity for managing disease progression in patients with DMD.

Cell fate specification is a critical process to generate cells with a wide range of characteristics from stem and progenitor cells. Emerging evidence demonstrates that the orphan nuclear receptor COUP-TFII serves as a key regulator in determining the cell identity during embryonic development. The present review summarizes our current knowledge on molecular mechanisms by which COUP-TFII employs to define the cell fates, with special emphasis on cardiovascular and renal systems. These novel insights pave the road for future studies of regenerative medicine.

Mitochondrial pyruvate carrier 1 (MPC1) and MPC 2 form a transporter complex in cells to control pyruvate transportation into mitochondria. Reduced expression of MPC1 disrupts the transporter function, induces metabolic shift to increase glycolysis, and thus plays important roles in several diseases, including cancer. However, the role of MPC1 in prostate cancer and the underlying mechanism causing the down-regulation of MPC1 in tumor cells remain to be defined. Here, we show that MPC1 serves as a critical regulator of glycolysis in prostate cancer cells, which in turn controls cancer cell growth, invasion, and the tumorigenic capability. More importantly, we identified that chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), a steroid receptor superfamily member, transcriptionally regulates the expression of MPC1. We further demonstrate that COUP-TFII, which is upregulated in the prostate cancer patient, regulates MPC1 and glycolysis to promote tumor growth and metastasis. Our findings reveal that COUP-TFII represses MPC1 expression in prostate cancer cells to facilitate a metabolism switch to increase glycolysis and promote cancer progression. This observation raises an intriguing possibility of targeting COUP-TFII to modulate cancer cell metabolism for prostate cancer intervention.

Parkinson’s disease (PD) is a neurodegenerative disorder featuring progressive loss of midbrain dopaminergic (DA) neurons that leads to motor symptoms. The etiology and pathogenesis of PD are not clear. We found that expression of COUP-TFII, an orphan nuclear receptor, in DA neurons is upregulated in PD patients through the analysis of public datasets. We show here that through epigenetic regulation, COUP-TFII contributes to oxidative stress, suggesting that COUP-TFII may play a role in PD pathogenesis. Elevated COUP-TFII expression specifically in DA neurons evokes DA neuronal loss in mice and accelerates the progression of phenotypes in a PD mouse model, MitoPark. Compared to control mice, those with elevated COUP-TFII expression displayed reduced cristae in mitochondria and enhanced cellular electron-dense vacuoles in the substantia nigra pars compacta. Mechanistically, we found that overexpression of COUP-TFII disturbs mitochondrial pathways, resulting in mitochondrial dysfunction. In particular, there is repressed expression of genes encoding cytosolic aldehyde dehydrogenases, which could enhance oxidative stress and interfere with mitochondrial function via 3,4-dihydroxyphenylacetaldehyde (DOPAL) buildup in DA neurons. Importantly, under-expression of COUP-TFII in DA neurons slowed the deterioration in motor functions of MitoPark mice. Taken together, our results suggest that COUP-TFII may be an important contributor to PD development and a potential therapeutic target., Author summary Parkinson’s disease (PD) is one of the major neurodegenerative diseases with increased risks in the elderly population. The patients mainly experience motor dysfunction, such as tremors, bradykinesia, rigid muscles, and impaired posture and balance. However, the underlying cause of PD is poorly defined in most cases. Understanding the etiology of PD will help prevention or treatment of this disease. Here, we reported that a transcription factor, COUP-TFII, is upregulated in the substantia nigra and dopaminergic neurons (DAs) of PD patients. Elevated expression of COUP-TFII leads to aberrant cell death of DAs, a group of neurons in the central nervous system that controls body movement. The underlying mechanism is enhanced oxidative stress due to COUP-TFII-mediated transcriptional repression of mitochondrial proteins for energy production and enzymes for detoxifying dopamine metabolites. Therefore, targeting COUP-TFII in dopaminergic neurons may be a potential therapeutic strategy for PD.

The makings of the reproductive tract Every embryo, regardless of its sex, contains both male and female primitive reproductive tracts before sexual differentiation. To establish a sex-specific reproductive system, female embryos need to remove the components of male tracts. The general consensus contends that removal of the male tracts occurs by default, a passive outcome owing to a lack of testis-derived androgens. Working in mice, Zhao et al. discovered that this process instead was actively promoted by the transcription factor COUP-TFII (see the Perspective by Swain). Without the action of this factor, embryos retained male reproductive tracts, independently of androgen action. These findings unveil unexpected mechanisms underlying the sexually dimorphic establishment of reproductive tracts. Science , this issue p. 717 ; see also p. 648

The transition from transcription initiation to elongation is a key regulatory step in gene expression, which requires RNA polymerase II (pol II) to escape promoter proximal pausing on chromatin. Although elongation factors promote pause release leading to transcription elongation, the role of epigenetic modifications during this critical transition step is poorly understood. Two histone marks on histone H3, lysine 4 trimethylation (H3K4me3) and lysine 9 acetylation (H3K9ac), co-localize on active gene promoters and are associated with active transcription. H3K4me3 can promote transcription initiation, yet the functional role of H3K9ac is much less understood. We hypothesized that H3K9ac may function downstream of transcription initiation by recruiting proteins important for the next step of transcription. Here, we describe a functional role for H3K9ac in promoting pol II pause release by directly recruiting the super elongation complex (SEC) to chromatin. H3K9ac serves as a substrate for direct binding of the SEC, as does acetylation of histone H4 lysine 5 to a lesser extent. Furthermore, lysine 9 on histone H3 is necessary for maximal pol II pause release through SEC action, and loss of H3K9ac increases the pol II pausing index on a subset of genes in HeLa cells. At select gene promoters, H3K9ac loss or SEC depletion reduces gene expression and increases paused pol II occupancy. We therefore propose that an ordered histone code can promote progression through the transcription cycle, providing new mechanistic insight indicating that SEC recruitment to certain acetylated histones on a subset of genes stimulates the subsequent release of paused pol II needed for transcription elongation.

Skeletal and cardiac muscles are the only striated muscles in the body. Although sharing many structural and functional similarities, skeletal and cardiac muscles have intrinsic differences in terms of physiology and regenerative potential. While skeletal muscle possesses a robust regenerative response, the mammalian heart has limited repair capacity after birth. In this review, we provide an updated view regarding chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) function in vertebrate myogenesis, with particular emphasis on the skeletal and cardiac muscles. We also highlight the new insights of COUP-TFII hyperactivity underlying striated muscle dysfunction. Lastly, we discuss the challenges and strategies in translating COUP-TFII action for clinical intervention.

Coactivator activator (CoAA) is a dual-functional coregulator that regulates steroid receptor-mediated transcription and alternative splicing. Previously, we have shown that CoAA has tumor-suppressive potential in tumorigenic human kidney cells. Here, we uncover a molecular mechanism by which Sjogren syndrome-associated autoantigen (SSA), an estrogen receptor (ER) coactivator, induces MYC oncogene by removing repressive CoAA through E2-dependent degradation of CoAA and promotes G(1)/S transition of the cell cycle as well as anchorage-independent growth capability of breast cancer cells. We also show that E2 and ER enhance the E3 ligase activity of SSA to modulate CoAA through splicing isoform-selective ubiquitylation. We propose this as one potential molecular basis for the reduced tumor incidence in autoimmune disease patients and suggest SSA as a potential therapeutic target to treat breast cancer.

The formation of complex organisms is highly dependent on the differentiation of specialized mature cells from common stem/progenitor cells. The orphan nuclear receptors chicken ovalbumin upstream promoter transcription factors (COUP-TFs) are broadly, but not ubiquitously, expressed in multiple tissues throughout embryonic development and COUP-TFs are indispensible for proper organogenesis. Recently, growing evidence suggests a critical role of COUP-TFs in multiple aspects of stem/progenitor cell biology. In this review, we highlight the progress of COUP-TFs function and its underlying mechanism in driving stem/progenitor cell self-renewal, lineage specification, differentiation, maintenance, and cell identity in diverse tissue types. These studies provide novel insights into future clinical utilities of COUP-TFs in stem cell based therapies and in the management of diseases.

Chromatin immunoprecipitation studies have mapped protein occupancies at many genomic loci. However, a detailed picture of the complexity of coregulators (CoRs) bound to a defined enhancer along with a transcription factor is missing. To address this, we used biotin-DNA pull-down assays coupled with mass spectrometry-immunoblotting to identify at least 17 CoRs from nuclear extracts bound to 17β-estradiol (E2)-liganded estrogen receptor-α on estrogen response elements (EREs). Unexpectedly, these complexes initially are biochemically stable and contain certain atypical corepressors. Addition of ATP dynamically converts these complexes to an "activated" state by phosphorylation events, primarily mediated by DNA-dependent protein kinase. Importantly, a "natural" ERE-containing enhancer and nucleosomal EREs recruit similar complexes. We further discovered the mechanism whereby H3K4me3 stimulates ERα-mediated transcription as compared with unmodified nucleosomes. H3K4me3 templates promote specific CoR dynamics in the presence of ATP and AcCoA, as manifested by CBP/p300 and SRC-3 dismissal and SAGA and TFIID stabilization/recruitment.

Epigenetic silencing of steroidogenic factor 1 (SF1) is lost in endometriosis, potentially contributing to de novo local steroidogenesis favoring inflammation and growth of ectopic endometrial tissue. In this study, we examine the impact of SF1 expression in the eutopic uterus by a novel mouse model that conditionally expresses SF1 in endometrium. In vivo SF1 expression promoted the development of enlarged endometrial glands and attenuated estrogen and progesterone responsiveness. Endometriosis induction by autotransplantation of uterine tissue to the mesenteric membrane resulted in the increase in size of ectopic lesions from SF1-expressing mice. By integrating the SF1-dependent transcriptome with the whole genome binding profile of SF1, we identified uterine-specific SF1-regulated genes involved in Wingless and Progesterone receptor-Hedgehog-Chicken ovalbumin upstream promoter transcription factor II signaling for gland development and epithelium-stroma interaction, respectively. The present results indicate that SF1 directly contributes to the abnormal uterine gland morphogenesis, an inhibition of steroid hormone signaling and activation of an immune response, in addition to previously postulated estrogen production.

Mutations in phosphatase and tensin homologue (PTEN) or genomic alterations in the phosphatidylinositol-3-OH kinase-signalling pathway are the most common genetic alterations reported in human prostate cancer. However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire metastatic potential remains poorly understood. Recent studies suggest that upregulation of transforming growth factor (TGF)-β signalling triggered by PTEN loss will form a growth barrier as a defence mechanism to constrain prostate cancer progression, underscoring that TGF-β signalling might represent a pre-invasive checkpoint to prevent PTEN-mediated prostate tumorigenesis. Here we show that COUP transcription factor II (COUP-TFII, also known as NR2F2), a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-β-dependent checkpoint for PTEN-null indolent tumours. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumour. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biological significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumour recurrence and disease progression, whereas it is inversely associated with TGF-β signalling. These findings reveal that the destruction of the TGF-β-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease, and supports COUP-TFII as a potential drug target for the intervention of metastatic human prostate cancer.

This study aimed to investigate the possible involvement of the orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) in the regulation of renin gene expression. COUP-TFII colocalized with renin in the juxtaglomerular cells of the kidney, which are the main source of renin in vivo. Protein-DNA binding studies demonstrated that COUP-TFII binds to an imperfect direct repeat COUP-TFII recognition sequence (termed hereafter proxDR) in the proximal renin promoter. Because cAMP signaling plays a central role in the control of the renin gene expression, we suggested that COUP-TFII may modulate this cAMP effect. Accordingly, knockdown of COUP-TFII in the clonal renin-producing cell lines As4.1 and Calu-6 diminished the stimulation of the renin mRNA expression by cAMP agonists. In addition, the mutation of the proxDR element in renin promoter reporter gene constructs abrogated the inducibility by cAMP. The proxDR sequence was found to be necessary for the function of a proximal renin promoter cAMP-response element (CRE). Knockdown of COUP-TFII or cAMP-binding protein (CREB), which is the archetypal transcription factor binding to CRE, decreased the basal renin gene expression. However, the deficiency of COUP-TFII did not further diminish the renin expression when CREB was knocked down. In agreement with the cell culture studies, mutant mice deficient in COUP-TFII have lower renin expression than their control strain. Altogether our data show that COUP-TFII is involved in the control of renin gene expression.

Chicken ovalbumin upstream promoter transcription factors (COUP-TFs) belong to the steroid/thyroid hormone receptor superfamily. Cloning of their cDNAs demonstrated the existence of two distinct but related genes: COUP-TFI (EAR-3, NR2F1) and COUP-TFII (ARP-1, NR2F2). They are referred to as orphan receptors because ligands for COUP-TFs have yet to be identified. Since 1998, extensive studies have demonstrated their physiological importance in cell-fate specification, organogenesis, angiogenesis, and metabolism, as well as a variety of diseases. In this article, we will comprehensively review the biological functions of COUP-TFII and its underlying mechanism in various developmental processes and diseases. In addition, we will briefly summarize some of the current findings of COUP-TFI.

Nuclear receptors and coregulators orchestrate diverse aspects of biological functions and inappropriate expression of these factors often associates with human diseases. The present study describes a conditional overexpression system consisting of a minigene located at the Rosa26 locus in the genome of mouse embryonic stem (ES) cells. Before activation, the minigene is silent due to a floxed STOP cassette inserted between the promoter and the transgene. Upon cre-mediated excision of the STOP cassette, the minigene constitutively expresses the tagged transgene driven by the ubiquitous CAGGS promoter. Thus, this system can be used to express target gene in any tissue in a spatial and/or temporal manner if respective cre mouse lines are available. Serving as proof of principle, the CAG-S-hCOUP-TFI allele was generated in ES cells and subsequently in mice. This allele was capable of conditionally overexpressing human chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) in all tissues tested upon activation by cre drivers. This allele was further subjected to address functionality of expressed COUP-TFI and the functional similarity between COUP-TFI and COUP-TFII. Expression of COUP-TFI in COUP-TFII-ablated uterus suppressed aberrant estrogen receptor-alpha activities and rescued implantation and decidualization defects of COUP-TFII mutants, suggesting that COUP-TFI and COUP-TFII are able to functionally compensate for each other in the uterus. A toolbox currently under construction will contain ES cell lines for overexpressing all 48 nuclear receptors and selected 10 coregulators. Upon completion, it will be a very valuable resource for the scientific community. Several ES cells are currently available for distribution.

Nuclear receptors and coregulators are multifaceted players in normal metabolic and homeostatic processes in addition to a variety of disease states including cancer, inflammation, diabetes, obesity, and atherosclerosis. Over the past 7 yr, the Nuclear Receptor Signaling Atlas (NURSA) research consortium has worked toward establishing a discovery-driven platform designed to address key questions concerning the expression, organization, and function of these molecules in a variety of experimental model systems. By applying powerful technologies such as quantitative PCR, high-throughput mass spectrometry, and embryonic stem cell manipulation, we are pursuing these questions in a series of transcriptomics-, proteomics-, and metabolomics-based research projects and resources. The consortium's web site (www.nursa.org) integrates NURSA datasets and existing public datasets with the ultimate goal of furnishing the bench scientist with a comprehensive framework for hypothesis generation, modeling, and testing. We place a strong emphasis on community input into the development of this resource and to this end have published datasets from academic and industrial laboratories, established strategic alliances with Endocrine Society journals, and are developing tools to allow web site users to act as data curators. With the ongoing support of the nuclear receptor and coregulator signaling communities, we believe that NURSA can make a lasting contribution to research in this dynamic field.

Adipose tissue development and function play a central role in the pathogenesis and pathophysiology of metabolic syndromes. Here, we show that chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) plays a pivotal role in adipogenesis and energy homeostasis. COUP-TFII is expressed in the early stages of white adipocyte development. COUP-TFII heterozygous mice (COUP-TFII(+/-)) have much less white adipose tissue (WAT) than wild-type mice (COUP-TFII(+/+)). COUP-TFII(+/-) mice display a decreased expression of key regulators for WAT development. Knockdown COUP-TFII in 3T3-L1 cells resulted in an increased expression of Wnt10b, while chromatin immunoprecipitation analysis revealed that Wnt10b is a direct target of COUP-TFII. Moreover, COUP-TFII(+/-) mice have increased mitochondrial biogenesis in WAT, and COUP-TFII(+/-) mice have improved glucose homeostasis and increased energy expenditure. Thus, COUP-TFII regulates adipogenesis by regulating the key molecules in adipocyte development and can serve as a target for regulating energy metabolism.

Endometrioid adenocarcinoma is the most frequent form of endometrial cancer, usually developing in pre- and peri-menopausal women. beta-catenin abnormalities are common in endometrioid type endometrial carcinomas with squamous differentiation. To investigate the role of beta-catenin (Ctnnb1) in uterine development and tumorigenesis, mice were generated which expressed a dominant stabilized beta-catenin or had beta-catenin conditionally ablated in the uterus by crossing the PR(Cre) mouse with the Ctnnb1(f(ex3)/+) mouse or Ctnnb1(f/f) mouse, respectively. Both of the beta-catenin mutant mice have fertility defects and the ability of the uterus to undergo a hormonally induced decidual reaction was lost. Expression of the dominant stabilized beta-catenin, PR(cre/+)Ctnnb1(f(ex3)/+), resulted in endometrial glandular hyperplasia, whereas ablation of beta-catenin, PR(cre/+)Ctnnb1(f/f), induced squamous cell metaplasia in the murine uterus. Therefore, we have demonstrated that correct regulation of beta-catenin is important for uterine function as well as in the regulation of endometrial epithelial differentiation.

In order for a successful pregnancy to occur, the embryo must attach to the luminal epithelial cells and invade into the stroma. Then, the surrounding stromal cells need to undergo decidualization in order to establish the vasculature necessary for survival of the embryo. These events in early pregnancy are tightly regulated by the steroid hormones, estrogen (E2) and progesterone (P4), through their cognate receptors, the estrogen receptor (ER) and the progesterone receptor (PR), respectively. Using a mouse model in which the PR has been ablated, it was demonstrated that the PR is necessary for embryo implantation and decidualization. Therefore, understanding the mechanism of PR action in the adult uterus is necessary in order to understand the events of early pregnancy. Insights from both mouse models and human samples have been integral in elucidating uterine PR action. These studies have shown that not only PR target genes, but also mediators of PR action are important for correct PR action in early pregnancy. Many of the genes involved in PR action in early pregnancy have also been shown to have roles in uterine diseases such as endometriosis and endometrial cancer. Therefore, the integration of mouse and human studies on PR action in the uterus will be important for the future understanding of uterine diseases and in the development of treatment for these diseases.