BRCA1 represses amphiregulin gene expression.
Ontology highlight
ABSTRACT:
SUBMITTER: Lamber EP
PROVIDER: S-EPMC2816672 | biostudies-literature | 2010 Feb
REPOSITORIES: biostudies-literature
Publications
BRCA1 represses amphiregulin gene expression.
Lamber Ekaterina P EP Horwitz Andrew A AA Parvin Jeffrey D JD
Cancer research 20100126 3
BRCA1, the breast cancer- and ovarian cancer-specific tumor suppressor, can be a transcriptional repressor or a transcriptional activator, depending on the promoter context. To identify the genes activated or repressed by BRCA1, we have analyzed microarray results from cells depleted of BRCA1 and revealed a number of genes regulated by BRCA1 on the level of transcription. Among the genes repressed by BRCA1, we have identified amphiregulin (AREG) and early growth response-1 (EGR1). Results indica ...[more]
Similar Datasets
Project description:The ?-catenin transcriptional coactivator is the key mediator of the canonical Wnt signaling pathway. In the absence of Wnt, ?-catenin associates with a cytosolic and multi-protein destruction complex where it is phosphorylated and targeted for proteasomal degradation. In the presence of Wnt, the destruction complex is inactivated and ?-catenin translocates into the nucleus. In the nucleus, ?-catenin binds T-cell factor (TCF) transcription factors to activate expression of c-MYC (MYC) and Axis inhibition protein 2 (AXIN2). AXIN2 is a member of the destruction complex and, thus, serves in a negative feedback loop to control Wnt/?-catenin signaling. AXIN2 is also present in the nucleus, but its function within this compartment is unknown. Here, we demonstrate that AXIN2 localizes to the nuclei of epithelial cells within normal and colonic tumor tissues as well as colorectal cancer cell lines. In the nucleus, AXIN2 represses expression of Wnt/?-catenin-responsive luciferase reporters and forms a complex with ?-catenin and TCF. We demonstrate that AXIN2 co-occupies ?-catenin/TCF complexes at the MYC promoter region. When constitutively localized to the nucleus, AXIN2 alters the chromatin structure at the MYC promoter and directly represses MYC gene expression. These findings suggest that nuclear AXIN2 functions as a rheostat to control MYC expression in response to Wnt/?-catenin signaling.
| S-EPMC3950968 | biostudies-literature
Project description:TG-interacting factor (Tgif1) represses gene expression by interaction with general corepressors, and can be recruited to target genes by transforming growth factor beta (TGF?) activated Smads, or by the retinoid X receptor (RXR). Here we show that Tgif1 interacts with the LXR? nuclear receptor and can repress transcription from a synthetic reporter activated by LXR?. In cultured cells reducing endogenous Tgif1 levels resulted in increased expression of LXR? target genes. To test the in vivo role of Tgif1, we analyzed LXR?-dependent gene expression in mice lacking Tgif1. In the livers of Tgif1 null mice, we observed significant derepression of the apolipoprotein genes, Apoa4 and Apoc2, suggesting that Tgif1 is an important in vivo regulator of apolipoprotein gene expression. In contrast, we observed relatively minimal effects on expression of other LXR target genes. This work suggests that Tgif1 can regulate nuclear receptor complexes, in addition to those containing retinoic acid receptors, but also indicates that there is some specificity to which NR target genes are repressed by Tgif1.
| S-EPMC2939915 | biostudies-literature
Project description:Translation initiation is a complex and highly regulated process that represents an important mechanism, controlling gene expression. eIF2A was proposed as an alternative initiation factor, however, its role and biological targets remain to be discovered. To further gain insight into the function of eIF2A in Saccharomyces cerevisiae, we identified mRNAs associated with the eIF2A complex and showed that 24% of the most enriched mRNAs encode proteins related to cell wall biogenesis and maintenance. In agreement with this result, we showed that an eIF2A deletion sensitized cells to cell wall damage induced by calcofluor white. eIF2A overexpression led to a growth defect, correlated with decreased synthesis of several cell wall proteins. In contrast, no changes were observed in the transcriptome, suggesting that eIF2A controls the expression of cell wall-related proteins at a translational level. The biochemical characterization of the eIF2A complex revealed that it strongly interacts with the RNA binding protein, Ssd1, which is a negative translational regulator, controlling the expression of cell wall-related genes. Interestingly, eIF2A and Ssd1 bind several common mRNA targets and we found that the binding of eIF2A to some targets was mediated by Ssd1. Surprisingly, we further showed that eIF2A is physically and functionally associated with the exonuclease Xrn1 and other mRNA degradation factors, suggesting an additional level of regulation. Altogether, our results highlight new aspects of this complex and redundant fine-tuned regulation of proteins expression related to the cell wall, a structure required to maintain cell shape and rigidity, providing protection against harmful environmental stress.
2023-09-15 | PXD043985 | Pride
Project description:Estrogen regulates over a thousand genes, with an equal number of them being induced or repressed. The distinct mechanisms underlying these dual transcriptional effects remain largely unknown. We derived comprehensive views of the transcription machineries assembled at estrogen-responsive genes through integrating multiple types of genomic data. In the absence of estrogen, the majority of genes formed higher-order chromatin structures, including DNA loops tethered to protein complexes involving RNA polymerase II (Pol II), estrogen receptor alpha (ERα) and ERα-pioneer factors. Genes to be 'repressed' by estrogen showed active transcription at promoters and throughout the gene bodies; genes to be 'induced' exhibited active transcription initiation at promoters, but with transcription paused in gene bodies. In the presence of estrogen, the majority of estrogen-induced genes retained the original higher-order chromatin structures, whereas most estrogen-repressed genes underwent a chromatin reconfiguration. For estrogen-induced genes, estrogen enhances transcription elongation, potentially through recruitment of co-activators or release of co-repressors with unique roles in elongation. For estrogen-repressed genes, estrogen treatment leads to chromatin structure reconfiguration, thereby disrupting the originally transcription-efficient chromatin structures. Our in silico studies have shown that estrogen regulates gene expression, at least in part, through modifying previously assembled higher-order complexes, rather than by facilitating de novo assembly of machineries.
| S-EPMC3783169 | biostudies-literature
Project description:High plasma concentrations of lipoprotein(a) [Lp(a), which is encoded by the APOA gene] increase an individual's risk of developing diseases, such as coronary artery diseases, restenosis, and stroke. Unfortunately, increased Lp(a) levels are minimally influenced by dietary changes or drug treatment. Further, the development of Lp(a)-specific medications has been hampered by limited knowledge of Lp(a) metabolism. In this study, we identified patients suffering from biliary obstructions with very low plasma Lp(a) concentrations that rise substantially after surgical intervention. Consistent with this, common bile duct ligation in mice transgenic for human APOA (tg-APOA mice) lowered plasma concentrations and hepatic expression of APOA. To test whether farnesoid X receptor (FXR), which is activated by bile acids, was responsible for the low plasma Lp(a) levels in cholestatic patients and mice, we treated tg-APOA and tg-APOA/Fxr-/- mice with cholic acid. FXR activation markedly reduced plasma concentrations and hepatic expression of human APOA in tg-APOA mice but not in tg-APOA/Fxr-/- mice. Incubation of primary hepatocytes from tg-APOA mice with bile acids dose dependently downregulated APOA expression. Further analysis determined that the direct repeat 1 element between nucleotides -826 and -814 of the APOA promoter functioned as a negative FXR response element. This motif is also bound by hepatocyte nuclear factor 4α (HNF4α), which promotes APOA transcription, and FXR was shown to compete with HNF4α for binding to this motif. These findings may have important implications in the development of Lp(a)-lowering medications.
| S-EPMC3163948 | biostudies-literature
Project description:Amphiregulin (AR) is a heparin-binding, heparin-inhibited member of the epidermal growth factor (EGF) family and an autocrine growth factor for human keratinocytes. Previous studies have shown that AR expression is increased in psoriatic epidermis. To test the hypothesis that aberrant AR expression is central to the development of psoriatic lesions, we constructed a transgene (K14-ARGE) encoding a human keratin 14 promoter-driven AR gene. Our results indicate that transgene integration and subsequent expression of AR in basal keratinocytes correlated with a psoriasis-like skin phenotype. Afflicted mice demonstrated shortened life spans, prominent scaling and erythematous skin with alopecia, and occasional papillomatous epidermal growths. Histologic examination revealed extensive areas of marked hyperkeratosis with focal parakeratosis, acanthosis, dermal and epidermal lymphocytic and neutrophilic infiltration, and dilated blood vessels within the papillary dermis. Our results reveal that AR exerts activity in the skin that is distinct from that of transgenic transforming growth factor-alpha or other cytokines, and induces skin pathology with striking similarities to psoriasis. Our observations also link the keratinocyte EGF receptor-ligand system to psoriatic inflammation, and suggest that aberrant expression of AR in the epidermis may represent a critical step in the development or propagation of psoriatic lesions.
| S-EPMC508424 | biostudies-other
Project description:Interleukin-2 (IL-2) is critical for T lymphocyte activation and regulated by many transcriptional factors. Prospero-related homeobox 1 (Prox1) is a multifunctional transcription factor, which can work as either a transcriptional activator or repressor depending on the cellular and developmental environment. We previously reported the Prox1 expression in T cells, raising the possibility of Prox1 involvement in the regulation of T cell function and IL-2 production. Here we demonstrated that the Prox1 expression in CD4+ T cells was downregulated by T cell receptor (TCR) activation. Overexpression of Prox1 attenuated IL-2 production, while knockdown of endogenous Prox1 by small interfering RNA increased IL-2 expression. Mechanistically, we showed that Prox1 inhibited the IL-2 promoter activity, and associated with the minimal IL-2 promoter. Prox1 repressed the nuclear factor of activated T cells 2 (NFAT2)-dependent transactivation of IL-2 gene by physically binding to NFAT2. The N-terminal region of Prox1 was essential for the binding and repression. In summary, our findings established Prox1 as a negative regulator in IL-2 gene expression through the direct interaction with NFAT2.
| S-EPMC5642489 | biostudies-literature
Project description:Background: Breast cancer is a complex disease, encompassed by different clinically and molecularly stratified entities. In 2000, Perou and colleagues demonstrated that tumor phenotypic diversity correlates with differences in global gene expression patterns, which in turn reflect aspects of the biological behavior of the tumors. Gene expression profiling has distinguished sporadic breast tumor sub-classes with genetic, histopathological and clinical differences, however, little is known about the molecular classification of hereditary breast tumors. It has been recently suggested that most tumors arising in BRCA1 mutation carriers display a basal-like phenotype, with the percentages reported in different studies ranging from 44 to almost 100%. In the present study we used expression profiling to produce a molecular classification of BRCA1-associated breast tumors and applied an integrative approach to examine biological dependencies or differences. Methods and Findings: We used frozen tumor tissue from fourteen patients all of which harbored germline pathological mutations in BRCA1. Total RNA extraction, amplification and labeling with Cy5 were performed using standard protocols. Universal Human Reference RNA (Stratagene) was used as a reference and labeled with Cy3. Each pair of Cy3/Cy5 samples was hybridized onto the CNIO human OncoChip V2, which consists of a spotted microarray with 11,675 cDNA clones from the I.M.A.G.E. Consortium. Two channel ratios (Cy5/Cy3) for each spot were generated and quantified using GenePix Pro 5.1 (Axon Instruments, Inc., Union City, CA, USA). Data were normalized and filtered and multiple statistical analyses were performed. The data are deposited in the GEO database under the accession number GSE12350. A tissue microarray (TMA) containing an independent series of 15 BRCA1 tumors was used to validate some of the results obtained. We have described molecular signatures that define BRCA1 subclasses depending on the expression of the gene encoding for Estrogen Receptor, ESR1. Signatures were found to be molecularly associated with different biological processes and transcriptional regulatory programs. The signature of ESR1-positive tumors was mainly linked to cell proliferation-related processes and, therefore, regulated by the estrogen receptor, while the signature of ESR1-negative tumors was mainly linked to the immune response and possibly regulated by transcription factors of the REL/NFκB family. These signatures were then verified in an independent series of hereditary and sporadic breast tumors, which revealed a possible prognostic value for each subclass. Over-expression of immune response genes appears to be a common feature of ER-negative sporadic and hereditary breast cancer and is associated with good prognosis. Interestingly, the ESR1-negative tumors were sub-stratified into two groups presenting light differences in the magnitude of the expression of immune response transcripts and REL/NFκB transcription factors, and this could be dependent on the type of germline alteration. In addition, analysis of the human protein-protein interaction network provides the wiring diagram of critical molecular associations in BRCA1 tumorigenesis and identifies close relationships between the different signatures. Conclusions: In summary, in the present study we have established the gene expression profiling of a series of BRCA1 tumors and found that there is a further degree of heterogeneity beyond the main classification by the expression of ESR1 and the presence or absence of a basal-like phenotype. We have identified specific signatures for ESR1-positive and ESR1-negative BRCA1 tumors, the latter characterized by the enrichment of immune response and cell cycle genes, and have found that slight differences in the level of expression of the immune response stratify the ESR1-negative BRCA1 tumors into two additional sub-groups (A and B) with possible prognostic differences. NFkB could be a major driver responsible for the levels of both immune response and apoptotic genes in this group of tumors, which could in turn be related to the type of germline mutation in BRCA1. This study reveals the molecular complexity of BRCA1 breast tumors, which are found to display similarities to sporadic tumors, and suggests possible prognostic implications. 14 samples (primary breast tumors containing a BRCA1 mutation) were hybridized to a cDNA microarray in order to investigate the possible heterogeneity within the BRCA1 group.
| S-ECPF-GEOD-12350 | biostudies-other
Project description:The Notch signaling pathway is a key regulator of stem cells during development, and its deregulated activity is linked to developmental defects and cancer. Transcriptional activation of Notch target genes requires cleavage of the Notch receptor in response to ligand binding, production of the Notch intracellular domain (NICD1), NICD1 migration into the nucleus, and assembly of a transcriptional complex. Post-translational modifications of Notch regulate its trafficking, turnover, and transcriptional activity. Here, we show that NICD1 is modified by small ubiquitin-like modifier (SUMO) in a stress-inducible manner. Sumoylation occurs in the nucleus where NICD1 is sumoylated in the RBPJ-associated molecule (RAM) domain. Although stress and sumoylation enhance nuclear localization of NICD1, its transcriptional activity is attenuated. Molecular modeling indicates that sumoylation can occur within the DNA-bound ternary transcriptional complex, consisting of NICD1, the transcription factor Suppressor of Hairless (CSL), and the co-activator Mastermind-like (MAML) without its disruption. Mechanistically, sumoylation of NICD1 facilitates the recruitment of histone deacetylase 4 (HDAC4) to the Notch transcriptional complex to suppress Notch target gene expression. Stress-induced sumoylation decreases the NICD1-mediated induction of Notch target genes, which was abrogated by expressing a sumoylation-defected mutant in cells and in the developing central nervous system of the chick in vivo. Our findings of the stress-inducible sumoylation of NICD1 reveal a novel context-dependent regulatory mechanism of Notch target gene expression.
| S-EPMC5864205 | biostudies-literature
Project description:The conserved INO80 chromatin remodeling complex is involved in regulation of DNA damage repair, replication and transcription. It is commonly recruited to the transcription start region and contributes to the establishment of promoter-proximal nucleosomes. We find a substantial influence of INO80 on nucleosome dynamics and gene expression during stress induced transcription. Transcription induced by osmotic stress leads to genome-wide remodeling of promoter proximal nucleosomes. INO80 function is required for timely return of evicted nucleosomes to the 5΄ end of induced genes. Reduced INO80 function in Arp8-deficient cells leads to correlated prolonged transcription and nucleosome eviction. INO80 and the related complex SWR1 regulate incorporation of the H2A.Z isoform at promoter proximal nucleosomes. However, H2A.Z seems not to influence osmotic stress induced gene regulation. Furthermore, we show that high rates of transcription promote INO80 recruitment to promoter regions, suggesting a connection between active transcription and promoter proximal nucleosome remodeling. In addition, we find that absence of INO80 enhances bidirectional promoter activity at highly induced genes and expression of a number of stress induced transcripts. We suggest that INO80 has a direct repressive role via promoter proximal nucleosome remodeling to limit high levels of transcription in yeast.
| S-EPMC5397147 | biostudies-literature