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Aneuploidy is a pervasive feature of cancer cells that results from chromosome missegregation. Several transcription factors have been associated with aneuploidy; however, no studies to date have demonstrated that mammalian transcription factors directly regulate chromosome segregation during mitosis. Here, we demonstrate that the ubiquitously expressed transcription factor specificity protein 1 (Sp1), which we have previously linked to aneuploidy, has a mitosis-specific role regulating chromosome segregation. We find that Sp1 localizes to mitotic centromeres and auxin-induced rapid Sp1 degradation at mitotic onset results in chromosome segregation errors and aberrant mitotic progression. Furthermore, rapid Sp1 degradation results in anomalous mitotic chromosome assembly characterized by loss of condensin complex I localization to mitotic chromosomes and chromosome condensation defects. Consistent with these defects, Sp1 degradation results in reduced chromosome passenger complex activity and histone H3 serine 10 phosphorylation during mitosis, which is essential for condensin complex I recruitment and chromosome condensation. Together, these data provide the first evidence of a mammalian transcription factor acting specifically during mitosis to regulate chromosome segregation.
Gasdermin-E (GSDME), the executioner of pyroptosis when cleaved by caspase 3, plays a crucial role in tumor defense and the response to chemotherapy drugs in cells. So far, there are poorly known mechanisms for the expression regulation of GSDME during cell death. Here, we identify the transcription factor Sp1 (Specificity protein 1) as a positive regulator of GSDME-mediated pyroptosis. Sp1 directly interacts with the GSDME promoter at -36 ~ -28 site and promotes GSDME gene transcription. Further, Sp1 knockdown or inhibition suppresses GSDME expression, thus reducing chemotherapy drugs (topotecan, etoposide, doxorubicin, sorafinib and cisplatin) induced cell pyroptosis. The regulation process synergizes with STAT3 (Signal transducer and activator of transcription 3) activity and antagonizes with DNA methylation but barely affects GSDMD-mediated pyroptosis or TNF-induced necroptosis. Our current finding reveals a new regulating mechanism of GSDME expression, which may be a viable target for the intervention of GSDME-dependent inflammatory diseases and cancer therapy.
Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) gene plays a crucial role in maintaining genomic stability, tumorigenesis and myogenesis. However, little is known about the regulatory elements governing the transcription of porcine ROCK1 gene. In the current study, the transcription start site (TSS) was identified by 5'-RACE, and was found to differ from the predicted one. The region in ROCK1 promoter which is critical for promoter activity was investigated via progressive deletions. Site-directed mutagenesis indicated that the region from -604 to -554 bp contains responsive elements for Sp1. Subsequent experiments showed that ROCK1 promoter activity is enhanced by Sp1 in a dose-dependent manner, whereas treatment with specific siRNA repressed ROCK1 promoter activity. Electrophoretic mobility shift assay (EMSA), DNA pull down and chromatin immunoprecipitation (ChIP) assays revealed Sp1 can bind to this region. qRT-PCR and Western blotting research followed by overexpression or inhibition of Sp1 indicate that Sp1 can affect endogenous ROCK1 expression at both mRNA and protein levels. Overexpression of Sp1 can promote the expression of myogenic differentiation 1(MyoD), myogenin (MyoG), myosin heavy chain (MyHC). Taken together, we conclude that Sp1 positively regulates ROCK1 transcription by directly binding to the ROCK1 promoter region (from -604 to -532 bp) and may affect the process of myogenesis.
The interferon γ-inducible protein 16 (IFI16) is known as immune sensor of retroviral DNA intermediates. We show that IFI16 restricts HIV-1 independently of immune sensing by binding and inhibiting the host transcription factor Sp1 that drives viral gene expression. This antiretroviral activity and ability to bind Sp1 require the N-terminal pyrin domain and nuclear localization of IFI16, but not the HIN domains involved in DNA binding. Highly prevalent clade C HIV-1 strains are more resistant to IFI16 and less dependent on Sp1 than other HIV-1 subtypes. Furthermore, inhibition of Sp1 by IFI16 or pharmacologically by Mithramycin A suppresses reactivation of latent HIV-1 in CD4+ T cells. Finally, IFI16 also inhibits retrotransposition of LINE-1, known to engage Sp1, and murine IFI16 homologs restrict Friend retrovirus replication in mice. Thus, IFI16 restricts retroviruses and retrotransposons by interfering with Sp1-dependent gene expression, and evasion from this restriction may facilitate spread of HIV-1 subtype C.
During animal development, the proper regulation of apoptosis requires the precise spatial and temporal execution of cell-death programs, which can include both caspase-dependent and caspase-independent pathways. Although the mechanisms of caspase-dependent and -independent cell killing have been examined extensively, how these pathways are coordinated within a single cell that is fated to die is unknown. Here we show that the Caenorhabditis elegans Sp1 transcription factor SPTF-3 specifies the programmed cell deaths of at least two cells-the sisters of the pharyngeal M4 motor neuron and the AQR sensory neuron-by transcriptionally activating both caspase-dependent and -independent apoptotic pathways. SPTF-3 directly drives the transcription of the gene egl-1, which encodes a BH3-only protein that promotes apoptosis through the activation of the CED-3 caspase. In addition, SPTF-3 directly drives the transcription of the AMP-activated protein kinase-related gene pig-1, which encodes a protein kinase and functions in apoptosis of the M4 sister and AQR sister independently of the pathway that activates CED-3 (refs 4, 5). Thus, a single transcription factor controls two distinct cell-killing programs that act in parallel to drive apoptosis. Our findings reveal a bivalent regulatory node for caspase-dependent and -independent pathways in the regulation of cell-type-specific apoptosis. We propose that such nodes might act as features of a general mechanism for regulating cell-type-specific apoptosis and could be therapeutic targets for diseases involving the dysregulation of apoptosis through multiple cell-killing mechanisms.
Disulfide-bond A oxidoreductase-like protein (DsbA-L) possesses beneficial effects such as promoting adiponectin multimerization and stability, increasing insulin sensitivity, and enhancing energy metabolism. The expression level of DsbA-L is negatively correlated with obesity in mice and humans, but the underlying mechanisms remain unknown. To address this question, we generated reporter gene constructs containing the promoter sequence of the mouse DsbA-L gene. Deletion analysis showed that the proximal promoter of mouse DsbA-L is located between -186 and -34 bp relative to the transcription start site. In silico analysis identified a putative Sp1 transcription factor binding site in the first intron of the DsbA-L gene. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that Sp1 bound to this intron region in vitro and in intact cells. Overexpression of Sp1 or suppressing Sp1 expression by siRNA reduced or increased DsbA-L promoter activity, respectively. The binding activity of Sp1 was gradually decreased during 3T3-L1 cell differentiation and was significantly increased in adipose tissues of obese mice. Our results identify Sp1 as an inhibitor of DsbA-L gene transcription, and the Sp1-mediated inhibition of DsbA-L gene expression may provide a mechanism underlying obesity-induced adiponectin downregulation and insulin resistance.
PSIP1 (PC4 and SFRS1 interacting protein 1) encodes two splice variants: lens epithelium-derived growth factor or p75 (LEDGF/p75) and p52. PSIP1 gene products were shown to be involved in transcriptional regulation, affecting a plethora of cellular processes, including cell proliferation, cell survival, and stress response. Furthermore, LEDGF/p75 has implications for various diseases and infections, including autoimmunity, leukemia, embryo development, psoriasis, and human immunodeficiency virus integration. Here, we reported the first characterization of the PSIP1 promoter. Using 5' RNA ligase-mediated rapid amplification of cDNA ends, we identified novel transcription start sites in different cell types. Using a luciferase reporter system, we identified regulatory elements controlling the expression of LEDGF/p75 and p52. These include (i) minimal promoters (-112/+59 and +609/+781) that drive the basal expression of LEDGF/p75 and of the shorter splice variant p52, respectively; (ii) a sequence (+319/+397) that may control the ratio of LEDGF/p75 expression to p52 expression; and (iii) a strong enhancer (-320/-207) implicated in the modulation of LEDGF/p75 transcriptional activity. Computational, biochemical, and genetic approaches enabled us to identify the transcription factor Sp1 as a key modulator of the PSIP1 promoter, controlling LEDGF/p75 transcription through two binding sites at -72/-64 and -46/-36. Overall, our results provide initial data concerning LEDGF/p75 promoter regulation, giving new insights to further understand its biological function and opening the door for new therapeutic strategies in which LEDGF/p75 is involved.
Klotho is a multifunctional protein, which exists both in a membrane bound and a soluble form. In renal tubules, Klotho is involved in cell senescence, anti-oxidant response, and renal fibrosis, thus regulation of its expression is critical to understand its roles in renal diseases. Indeed, reduced expression was observed in various renal disease. However, the mechanisms underlying transcriptional regulation of the human klotho gene (KL) largely remain unknown.
Dok-7 is a cytoplasmic activator of the muscle-specific receptor tyrosine kinase MuSK, and these two proteins are essential for neuromuscular junction (NMJ) formation. Mutations of the human DOK7 gene underlie a limb-girdle type of congenital myasthenic syndrome, a group of disorders characterized by NMJ synaptopathy. Because MuSK governs postsynaptic specialization of NMJs and controls where the NMJ forms in the skeletal muscle, it is crucial to appropriately regulate when and where Dok-7 is expressed to activate MuSK. However, the mechanisms underlying expression of the dok-7 gene remain unclear. Here, we show that two Sp1 consensus sequences in the mouse dok-7 5'-flanking region are necessary for dok-7 gene expression in muscle cells. We further demonstrate that the transcription factor Sp1 activates dok-7 gene expression through interaction with these two Sp1 sites. Taken together, these results indicate that Sp1 plays a crucial role in the regulation of the dok-7 gene.
Pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in the placenta, where it functions as an autocrine hormone. The synthesis of leptin in normal trophoblastic cells is regulated by different endogenous biochemical agents, but the regulation of placental leptin expression is still poorly understood. We have previously reported that 17β-estradiol up-regulates placental leptin expression through genomic and nongenomic mechanisms.
Colorectal cancer occurs throughout the world but is most common in developed countries. Cancer progression is believed to be driven by genetic mutations in this complex condition. Risk factors for developing colorectal cancer include a genetic family history, long-term ulcerative colitis, and colonic polyps. The use of baicalin has been reported to be clinically efficacious against colon tumors in Asian countries despite an unclear mechanism of action. Several cancers have been found to be biologically dependent on the specificity protein 1 (sp1) transcription factor family. We hypothesized that baicalin may exert its chemotherapeutic effects by sp1 downregulation. Using the SW480 human colorectal cancer cell line, we investigated the physiological properties of baicalin. Our experiments were designed toward clarifying three goals: (a) to determine the mRNA expression profile of transcription factors in colorectal cancer patients using a microarray-based analysis; (b) to determine the effects of baicalin on the sp1 transcription factor with western blotting and reporter cell assays; and (c) to contrast the effects of mithramycin-A (an sp1 transcription factor inhibitor) and baicalin using western blotting and reporter cell assays. Both baicalin and mithramycin-A downregulated sp1 expression, attenuated SW480 cell proliferation, and increased cell apoptosis. Baicalin inhibited sp1 expression and led to SW480 apoptosis, thus clarifying the effect of this traditional Chinese medicine compound in the treatment of colon cancer.
The ubiquitous transcription factor Sp1 regulates the expression of a vast number of genes involved in many cellular functions ranging from differentiation to proliferation and apoptosis. Sp1 expression levels show a dramatic increase during transformation and this could play a critical role for tumour development or maintenance. Although Sp1 deregulation might be beneficial for tumour cells, its overexpression induces apoptosis of untransformed cells. Here we further characterised the functional and transcriptional responses of untransformed cells following Sp1 overexpression.
Loss of polarity protein Par3 promotes breast cancer tumorigenesis and metastasis. The underlying molecular mechanisms of Par3 down-regulation and related prognostic significance in breast cancer remain unclear. Here, we discovered that Par3 down-regulation was associated with shorter relapse-free survival in Luminal A subtype of breast cancer. Par3 knockdown promoted breast cancer cells migration and invasion. Importantly, we identified that transcription factor Sp1 bound to PARD3 promoter region and induced Par3 expression. Breast cancer patients with low Sp1 showed significantly worse RFS and low expression level of Par3. Par3 over-expression partially reversed Sp1 knockdown induced migration and invasion. Together, decreased Sp1 level mediates Par3 down-regulation, which correlated with poor prognosis of ER + breast cancer patients, via reduced binding with PARD3 promoter.
Angiogenesis is recognized as an important hallmark of cancer. Although telomerase is thought to be involved in tumor angiogenesis, the evidence and underlying mechanism remain elusive. Here, we demonstrate that human telomerase reverse transcriptase (hTERT) activates vascular epithelial growth factor (VEGF) gene expression through interactions with the VEGF promoter and the transcription factor Sp1. hTERT binds to Sp1 in vitro and in vivo and stimulates angiogenesis in a manner dependent on Sp1. Deletion of the mTert gene in the first generation of Tert null mice compromised tumor growth, with reduced VEGF expression. In addition, we show that hTERT expression levels are positively correlated with those of VEGF in human gastric tumor samples. Together, our results demonstrate that hTERT facilitates tumor angiogenesis by up-regulating VEGF expression through direct interactions with the VEGF gene and the Sp1 transcription factor. These results provide novel insights into hTERT function in tumor progression in addition to its role in telomere maintenance.
Roundabout4 (Robo4) is a gene that is expressed specifically in vasculature and is involved in the angiogenesis and integrity of blood vessels. The expression level of Robo4 increases gradually along with the development of diabetic retinopathy (DR). In this study, we explored the mechanism of transcriptional regulation of Robo4 in retinal endothelial cells, and investigated the effects of this regulation on cellular functions under hyperglycemic conditions. Human retinal endothelial cells (HREC) exposed to hyperglycemia were used to detect the expression levels of specificity protein 1 (SP1) and Robo4 by RT-qPCR and western blotting. Small interfering RNA (SiRNA) transfection technology was used to analyze the regulatory relationship between SP1 and Robo4. The effect of transcription factor SP1 on Robo4 promoter activity and the location of SP1 binding sites were investigated using chromatin immunoprecipitation (ChIP) and luciferase assay. Cell migration, monolayer permeability and tube formation assays were performed to demonstrate the role of SP1/Robo4 in regulating HREC functions in hyperglycemic conditions. The results showed that hyperglycemia upregulated the mRNA and protein levels of SP1 and Robo4 in HREC. Depletion of SP1 by siRNA transfection inhibited the hyperglycemia induced overexpression of Robo4. ChIP combined with luciferase assay showed that under hyperglycemic conditions, SP1 significantly increased the transcriptional level of Robo4 via an additional SP1 binding site at -1912/-1908 in the Robo4 promoter. Repressing the SP1/Robo4 pathway effectively mitigated the abnormity in HREC migration, permeability and angiogenesis induced by hyperglycemia. All these findings indicate that hyperglycemia-induced upregulation of Robo4 is mediated by enhanced transcription of SP1. The SP1/Robo4 signaling pathway can regulate the migratory ability, monolayer permeability and angiogenesis of HREC under hyperglycemic conditions, suggesting that it may play an important role in microvascular dysfunction during DR.
Specificity protein 1 (Sp1) is an important transcription factor implicated in numerous cellular processes. However, whether Sp1 is involved in the regulation of RNA polymerase III (Pol III)-directed gene transcription in human cells remains unknown. Here, we first show that filamin A (FLNA) represses Sp1 expression as well as expression of TFIIB-related factor 1 (BRF1) and general transcription factor III C subunit 2 (GTF3C2) in HeLa, 293T, and SaOS2 cell lines stably expressing FLNA-silencing shRNAs. Both BRF1 promoter 4 (BRF1P4) and GTF3C2 promoter 2 (GTF3C2P2) contain putative Sp1-binding sites, suggesting that Sp1 affects Pol III gene transcription by regulating BRF1 and GTF3C2 expression. We demonstrate that Sp1 knockdown inhibits Pol III gene transcription, BRF1 and GTF3C2 expression, and the proliferation of 293T and HeLa cells, whereas Sp1 overexpression enhances these activities. We obtained a comparable result in a cell line in which both FLNA and Sp1 were depleted. These results indicate that Sp1 is involved in the regulation of Pol III gene transcription independently of FLNA expression. Reporter gene assays showed that alteration of Sp1 expression affects BRF1P4 and GTF3C2P2 activation, suggesting that Sp1 modulates Pol III-mediated gene transcription by controlling BRF1 and GTF3C2 gene expression. Further analysis revealed that Sp1 interacts with and thereby promotes the occupancies of TATA box-binding protein, TFIIAα, and p300 at both BRF1P4 and GTF3C2P2. These findings indicate that Sp1 controls Pol III-directed transcription and shed light on how Sp1 regulates cancer cell proliferation.
Deregulated expression of oncogenes or transcription factors such as specificity protein 1 (Sp1) is observed in many human cancers and plays a role in tumor maintenance. Paradoxically in untransformed cells, Sp1 overexpression induces late apoptosis but the early intrinsic response is poorly characterized. In the present work, we studied increased Sp1 level consequences in untransformed cells and showed that it turns on an early innate immune transcriptome. Sp1 overexpression does not activate known cellular stress pathways such as DNA damage response or endoplasmic reticulum stress, but induces the activation of the OAS-RNase L pathway and the generation of small self-RNAs, leading to the upregulation of genes of the antiviral RIG-I pathway at the transcriptional and translational levels. Finally, Sp1-induced intrinsic innate immune response leads to the production of the chemokine CXCL4 and to the recruitment of inflammatory cells in vitro and in vivo. Altogether our results showed that increased Sp1 level in untransformed cells constitutes a novel danger signal sensed by the OAS-RNase L axis leading to the activation of the RIG-I pathway. These results suggested that the OAS-RNase L-RIG-I pathway may be activated in sterile condition in absence of pathogen.
Fibrosis disrupts tissue balance and links to severe illnesses, impairing organ function and, in some cases, even fatality. The interaction between M2 macrophages and fibroblasts is vital for tissue equilibrium. Transforming growth factor β1 (TGF-β1) released by M2 macrophages plays a central role in fibrosis, regulating fibroblast activity and extracellular matrix metabolism. Targeting TGF-β1 is key to fibrosis treatment. In our study using three fibroblast cell lines, we reveal that the M2 macrophage transcription factor SP1 enhances binding to the TGF-β1 promoter motif, promoting TGF-β1 transcription and activating fibroblasts (This process does not involve changes in DNA methylation levels surrounding the motif sequence). The zinc fingers in SP1's DNA-binding domain 3 are crucial for this binding. In vivo, targeting SP1 in rat ligaments significantly reduces extracellular matrix accumulation. Our findings highlight SP1 as a promising target for regulating tissue extracellular matrix and combating fibrosis.
Nuclear factors of activated T-cells (NFATs) have been mainly characterized in the context of immune response regulation because, as transcription factors, they have the ability to induce gene transcription. NFAT proteins are found in several types of tumors, for instance, pancreatic carcinoma. The role of NFATs in carcinogenesis is regulating central genes in cell differentiation and cell growth. NFAT proteins are primarily located in cytoplasm and only transported to the cell nucleus after activation. Here, they interact with other transcription factors cooperating with NFAT proteins, thus influencing the selection and regulation of NFAT-controlled genes. To identify and characterize possible interaction partners of the transcription factor NFATc2 in pancreatic carcinoma cells PaTu 8988t.
GDP-fucose transporter plays a crucial role in fucosylation of glycoproteins by providing activated fucose donor, GDP-fucose, for fucosyltransferases in the lumen of the Golgi apparatus. Fucose-containing glycans are involved in many biological processes, which are essential for growth and development. Mutations in the GDP-fucose transporter gene cause leukocyte adhesion deficiency syndrome II, a disease characterized by slow growth, mental retardation and immunodeficiency. However, no information is available regarding its transcriptional regulation. Here, by using human cells, we show that TGF-β1 specifically induces the GDP-fucose transporter expression, but not other transporters tested such as CMP-sialic acid transporter, suggesting a diversity of regulatory pathways for the expression of these transporters. The regulatory elements that are responsive to the TGF-β1 stimulation are present in the region between bp -330 and -268 in the GDP-fucose transporter promoter. We found that this region contains two identical octamer GC-rich motifs (GGGGCGTG) that were demonstrated to be essential for the transporter expression. We also show that the transcription factor Sp1 specifically binds to the GC-rich motifs in vitro and Sp1 coupled with phospho-Smad2 is associated with the promoter region covering the Sp1-binding motifs in vivo using chromatin immunoprecipitation (ChIP) assays. In addition, we further confirmed that Sp1 is essential for the GDP-fucose transporter expression stimulated by TGF-β1 using a luciferase reporter system. These results highlight the role of TGF-β signaling in regulation of the GDP-fucose transporter expression via activating Sp1. This is the first transcriptional study for any nucleotide sugar transporters that have been identified so far. Notably, TGF-β1 receptor itself is known to be modified by fucosylation. Given the essential role of GDP-fucose transporter in fucosylation, the finding that TGF-β1 stimulates the expression of this transporter, suggests a possible intracellular link between the function of nucleotide sugar transporter and the TGF-β signaling pathway.
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