Search Results (7)

This review focuses on the pivotal roles of nuclear receptors (NRs) in driving endocrine resistance in prostate and breast cancers. In prostate cancer (PCa), androgen receptor (AR) amplification, mutations, and altered coactivator interactions sustain tumor growth under androgen deprivation therapy (ADT), leading to castration-resistant prostate cancer (CRPC). Orphan NRs like RORβ, TLX, and COUP-TFII further contribute to CRPC by regulating stemness and therapeutic resistance mechanisms. In breast cancer, NRs, including estrogen receptor alpha (ERα), androgen receptor (AR), glucocorticoid receptor (GR), and liver receptor homolog-1 (LRH-1), modulate estrogen signaling pathways and alternative survival mechanisms like PI3K/AKT/mTOR and NFκB, promoting resistance to endocrine therapies such as tamoxifen. Understanding these NR-mediated mechanisms is critical for developing targeted therapies to overcome endocrine resistance and improve patient outcomes in hormone-dependent cancers. Full article

Mutations in the transcription factor-coding gene SOX18, the growth factor-coding gene VEGFC and its receptor-coding gene VEGFR3/FLT4 cause primary lymphedema in humans. In mammals, SOX18, together with COUP-TFII/NR2F2, activates the expression of Prox1, a master regulator in lymphatic identity and development. Knockdown studies have also suggested an involvement of Sox18, Coup-tfII/Nr2f2, and Prox1 in zebrafish lymphatic development. Mutants in the corresponding genes initially failed to recapitulate the lymphatic defects observed in morphants. In this paper, we describe a novel zebrafish sox18 mutant allele, sa12315, which behaves as a null. The formation of the lymphatic thoracic duct is affected in sox18 homozygous mutants, but defects are milder in both zygotic and maternal-zygotic sox18 mutants than in sox18 morphants. Remarkably, in sox18 mutants, the expression of the closely related sox7 gene is elevated where lymphatic precursors arise. Sox7 could thus mask the absence of a functional Sox18 protein and account for the mild lymphatic phenotype in sox18 mutants, as shown in mice. Partial knockdown of vegfc exacerbates lymphatic defects in sox18 mutants, making them visible in heterozygotes. Our data thus reinforce the genetic interaction between Sox18 and Vegfc in lymphatic development, previously suggested by knockdown studies, and highlight the ability of Sox7 to compensate for Sox18 lymphatic dysfunction. Full article

The peptide hormone insulin-like 3 (INSL3) is produced almost exclusively by Leydig cells of the male gonad. INSL3 has several functions such as fetal testis descent and bone metabolism in adults. Insl3 gene expression in Leydig cells is not hormonally regulated but rather is constitutively expressed. The regulatory region of the Insl3 gene has been described in various species; moreover, functional studies have revealed that the Insl3 promoter is regulated by various transcription factors that include the nuclear receptors AR, NUR77, COUP-TFII, LRH1, and SF1, as well as the Krüppel-like factor KLF6. However, these transcription factors are also found in several tissues that do not express Insl3, indicating that other, yet unidentified factors, must be involved to drive Insl3 expression specifically in Leydig cells. Through a fine functional promoter analysis, we have identified a 35-bp region that is responsible for conferring 70% of the activity of the mouse Insl3 promoter in Leydig cells. All tri- and dinucleotide mutations introduced dramatically reduced Insl3 promoter activity, indicating that the entire 35-bp sequence is required. Nuclear proteins from MA-10 Leydig cells bound specifically to the 35-bp region. The 35-bp sequence contains GC- and GA-rich motifs as well as potential binding elements for members of the CREB, C/EBP, AP1, AP2, and NF-κB families. The Insl3 promoter was indeed activated 2-fold by NF-κB p50 but not by other transcription factors tested. These results help to further define the regulation of Insl3 gene transcription in Leydig cells. Full article

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) is an orphan nuclear hormone receptor of unknown ligands. This molecule has two interesting features: (1) it is a developmental gene, and (2) it is a potential hormone receptor. Here, we describe the possible roles of COUP-TFII in the organogenesis of the kidneys and protection from adult renal diseases, primarily in mouse models. COUP-TFII is highly expressed in embryos, including primordial kidneys, and is essential for the formation of metanephric mesenchyme and the survival of renal precursor cells. Although the expression levels of COUP-TFII are low and its functions are unknown in healthy adults, it serves as a reno-protectant molecule against acute kidney injury. These are good examples of how developmental genes exhibit novel functions in the etiology of adult diseases. We also discuss the ongoing research on the roles of COUP-TFII in podocyte development and diabetic kidney disease. In addition, the identification of potential ligands suggests that COUP-TFII might be a novel therapeutic target for renal diseases in the future. Full article

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known for mediating the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Although the canonical mechanism of AhR activation involves heterodimerization with the aryl hydrocarbon receptor nuclear translocator, other transcriptional regulators that interact with AhR have been identified. Enrichment analysis of motifs in AhR-bound genomic regions implicated co-operation with COUP transcription factor (COUP-TF) and hepatocyte nuclear factor 4 (HNF4). The present study investigated AhR, HNF4α and COUP-TFII genomic binding and effects on gene expression associated with liver-specific function and cell differentiation in response to TCDD. Hepatic ChIPseq data from male C57BL/6 mice at 2 h after oral gavage with 30 µg/kg TCDD were integrated with bulk RNA-sequencing (RNAseq) time-course (2–72 h) and dose–response (0.01–30 µg/kg) datasets to assess putative AhR, HNF4α and COUP-TFII interactions associated with differential gene expression. Functional enrichment analysis of differentially expressed genes (DEGs) identified differential binding enrichment for AhR, COUP-TFII, and HNF4α to regions within liver-specific genes, suggesting intersections associated with the loss of liver-specific functions and hepatocyte differentiation. Analysis found that the repression of liver-specific, HNF4α target and hepatocyte differentiation genes, involved increased AhR and HNF4α binding with decreased COUP-TFII binding. Collectively, these results suggested TCDD-elicited loss of liver-specific functions and markers of hepatocyte differentiation involved interactions between AhR, COUP-TFII and HNF4α. Full article

The nuclear receptors (NRs) belong to a vast family of evolutionary conserved proteins acting as ligand-activated transcription factors. Functionally, NRs are essential in embryogenesis and organogenesis and in adulthood they are involved in almost every physiological and pathological process. Our knowledge of NRs action has greatly improved in recent years, demonstrating that both their expression and activity are tightly regulated by a network of signaling pathways, miRNA and reciprocal interactions. The Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII, NR2F2) is a NR classified as an orphan due to the lack of a known natural ligand. Although its expression peaks during development, and then decreases considerably, in adult tissues, COUP-TFII is an important regulator of differentiation and it is variably implicated in tissues homeostasis. As such, alterations of its expression or its transcriptional activity have been studied and linked to a spectrum of diseases in organs and tissues of different origins. Indeed, an altered COUP-TFII expression and activity may cause infertility, abnormality in the vascular system and metabolic diseases like diabetes. Moreover, COUP-TFII is actively investigated in cancer research but its role in tumor progression is yet to be fully understood. In this review, we summarize the current understanding of COUP-TFII in healthy and pathological conditions, proposing an updated and critical view of the many functions of this NR. Full article

The orphan receptors COUP-TFI and COUP-TFII are members of the nuclear receptor superfamily that play distinct and critical roles in vertebrate organogenesis, as demonstrated by loss-of-function COUP-TFI and/or COUP-TFII mutant mice. Although COUP-TFs are expressed in a wide range of tissues in adults, little is known about their functions at later stages of development or in organism homeostasis. COUP-TFs are expressed in cancer cell lines of various origins and increasing studies suggest they play roles in cell fate determination and, potentially, in cancer progression. Nevertheless, the exact roles of COUP-TFs in these processes remain unclear and even controversial. In this review, we report both in vitro and in vivo data describing known and suspected actions of COUP-TFs that suggest that these factors are involved in modification of the phenotype of cancer cells, notably of epithelial origin. Full article