Transcription factor TFE3 enhances cell cycle and cancer progression by binding to the hTERT promoter.
Ontology highlight
ABSTRACT:
SUBMITTER: Miao B
PROVIDER: S-EPMC8696226 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:To ensure genome stability, DNA must be replicated once and only once during each cell cycle. Cdt1 is tightly regulated to make sure that cells do not rereplicate their DNA. Multiple regulatory mechanisms operate to ensure degradation of Cdt1 in S phase. However, little is known about the positive regulators of Cdt1 under physiological conditions. Here we identify FOXO3 as a binding partner of Cdt1. FOXO3 forms a protein complex with Cdt1, which in turn blocks its interaction with DDB1 and PCNA. Conversely, FOXO3 depletion facilitated the proteolysis of Cdt1 in unperturbed cells. Intriguingly, FOXO3 deficiency resulted in impaired S-phase entry and reduced cell proliferation. We provide data that FOXO3 knockdown mimics Cdt1 down-regulation and affects G1/S transitions. Our results demonstrate a unique role of FOXO3 in binding to Cdt1 and maintaining its level required for cell cycle progression.
| S-EPMC3326503 | biostudies-literature
Project description:A cyclical control circuit composed of four master regulators drives the Caulobacter cell cycle. We report that SciP, a helix-turn-helix transcription factor, is an essential component of this circuit. SciP is cell cycle-controlled and co-conserved with the global cell cycle regulator CtrA in the ?-proteobacteria. SciP is expressed late in the cell cycle and accumulates preferentially in the daughter swarmer cell. At least 58 genes, including many flagellar and chemotaxis genes, are regulated by a type 1 incoherent feedforward motif in which CtrA activates sciP, followed by SciP repression of ctrA and CtrA target genes. We demonstrate that SciP binds to DNA at a motif distinct from the CtrA binding motif that is present in the promoters of genes co-regulated by SciP and CtrA. SciP overexpression disrupts the balance between activation and repression of the CtrA-SciP coregulated genes yielding filamentous cells and loss of viability. The type 1 incoherent feedforward circuit motif enhances the pulse-like expression of the downstream genes, and the negative feedback to ctrA expression reduces peak CtrA accumulation. The presence of SciP in the control network enhances the robustness of the cell cycle to varying growth rates.
| S-EPMC2973855 | biostudies-literature
Project description:Background. The computational identification of functional transcription factor binding sites (TFBSs) remains a major challenge of computational biology. Results. We have analyzed the conserved promoter sequences for the complete set of human RefSeq genes using our conserved transcription factor binding site (CONFAC) software. CONFAC identified 16296 human-mouse ortholog gene pairs, and of those pairs, 9107 genes contained conserved TFBS in the 3 kb proximal promoter and first intron. To attempt to predict in vivo occupancy of transcription factor binding sites, we developed a novel marginal effect isolator algorithm that builds upon Bayesian methods for multigroup TFBS filtering and predicted the in vivo occupancy of two transcription factors with an overall accuracy of 84%. Conclusion. Our analyses show that integration of chromatin immunoprecipitation data with conserved TFBS analysis can be used to generate accurate predictions of functional TFBS. They also show that TFBS cooccurrence can be used to predict transcription factor binding to promoters in vivo.
| S-EPMC2768302 | biostudies-literature
Project description:Controversy remains about the identity of the transcription factor(s) (TFs), which bind to the two E-box elements (CACGTG, proximal and distal) of the human telomerase (hTERT) gene promoter, the essential elements in the regulation of telomerase. Here, systematic oligonucleotide trapping supplemented with 2-DE and proteomic methods was used to identify E-box binding TFs. Although insufficient purity was obtained from the proximal E-box element trapping, further fractionation provided by 2-DE and specific identification from Southwestern blotting analysis allow us to clearly identify an E-box binding TF. The protein spot was cut from 2-DE and in-gel digested with trypsin for LC-nanospray ESI-MS/MS analysis. This identified upstream stimulatory factor 2 (USF2). Western blotting analysis with specific antibodies clearly shows USF2 present in the purified fraction and USF2 antibody supershifts the specific DNA-binding complex on non-denaturing gels. Furthermore, a novel method was developed in which the specific DNA-TF complex was separated on a non-denaturing gel, the band was cut and applied to SDS-PAGE for a second dimension. Western blots of this second gel also confirmed the presence of USF2.
| S-EPMC2851252 | biostudies-literature
Project description:The NFAT family of transcription factors has been primarily related to T cell development, activation, and differentiation. Further studies have shown that these ubiquitous proteins are observed in many cell types inside and outside the immune system, and are involved in several biological processes, including tumor growth, angiogenesis, and invasiveness. However, the specific role of the NFAT1 family member in naive B cell proliferation remains elusive. Here, we demonstrate that NFAT1 transcription factor controls Cyclin E expression, cell proliferation, and tumor growth in vivo. Specifically, we show that inducible expression of NFAT1 inhibits cell cycle progression, reduces colony formation, and controls tumor growth in nude mice. We also demonstrate that NFAT1-deficient naive B lymphocytes show a hyperproliferative phenotype and high levels of Cyclin E1 and E2 upon BCR stimulation when compared to wild-type B lymphocytes. NFAT1 transcription factor directly regulates Cyclin E expression in B cells, inhibiting the G1/S cell cycle phase transition. Bioinformatics analysis indicates that low levels of NFAT1 correlate with high expression of Cyclin E1 in different human cancers, including Diffuse Large B-cell Lymphomas (DLBCL). Together, our results demonstrate a repressor role for NFAT1 in cell cycle progression and Cyclin E expression in B lymphocytes, and suggest a potential function for NFAT1 protein in B cell malignancies.
| S-EPMC5004684 | biostudies-literature
Project description:The non-coding genome contributes substantially to the total cellular DNA mass and is thoutht to host regulatory cis-acting element, but may also code for some regulatory transcripts. Despite ist contribution to the genomic mass, it has barely recieved scientific attention. Much emphasis has been laid on the approximaetly 2% coding Region, although its transcription, in most cases is regulated at the level of the non-coding genome. In recent years, several studies have revealed disease-associated somatic mutations in regulatory regions of the non-coding genome. One most prominent example is the hotspot mutations in the core promoter region of the TERT gene. In several cancer entities, these alterations have been associated with dysregulation of telomerase activity and tumorigenesis. Novel binding sites are created for transcription factors of the ETS family and GABP for example has been shown to bind to these novel ETS sites. The entire spectrum of ETS family members that can bind is however still lacking. In ordert o fill this knowledge gap and understand the impact of such binding on tumor biology, we have used functional protein microarrays to identify ETS members that preferentially bind the mutant promoter and by means of transcription profiling, we have identified downstream targets of the binding events. We have used siRNA to knockdown FLI-1 and hTERT in cell lines from three cancer entities (NSCLC, PDAC and MCC) with the help oft he illumina beadchip arrays and we compared the transcriptional profiles of the cell lines under different knockdown conditions. We Identify CCND1 and E2F2 as direct targets of both TERT and FLI-1, and CMTM7 as an FLI1-only target. We show, for different cancer entities, that FLI-1 binds the TERT promoter and accelerates progression through the cell cycle by enhancing E2F2 and CCND1 expression
2019-06-10 | E-MTAB-7452 | biostudies-arrayexpress
Project description:Glioblastoma multiforme (GBM) is an extraordinary aggressive disease that requires more effective therapeutic options. In the past few years, many microRNAs (miRNAs) have been demonstrated to have important roles in promoting GBM progression. However, little is known about the role of miR-1179 in GBM. In the present study, we found that miR-1179 was significantly downregulated in glioma tissues and cell lines. Functional experiments showed that introduction of miR-1179 dramatically suppressed GBM cell proliferation and cell cycle progression. Importantly, treatment of miR-1179 strongly inhibited tumor growth in a subcutaneous GBM model. Further studies showed that E2F transcription factor 5 (E2F5), a key transcription factor that controls cell cycle transition, was a direct target of miR-1179. Silencing of E2F5 inhibited the proliferative ability of GBM cells and induces cell cycle arrest, which were consistent with the effects of miR-1179 overexpression. More importantly, reintroduction of E2F5 into GBM cells reversed the tumor-suppressive function of miR-1179. Finally, we demonstrated that miR-1179 expression was negatively correlated with E2F5 messenger RNA (mRNA) levels in high-grade gliomas. Our findings provide new insights into the role of miR-1179 in the progression of GBM, and implicate the potential application of miR-1179 in GBM therapy.
| S-EPMC5574940 | biostudies-literature
Project description:SDHD encodes subunit D of the succinate dehydrogenase complex, an integral membrane protein. Across cancer types, recurrent SDHD promoter mutations were reported to occur exclusively in melanomas, at a frequency of 4% to 5%. These mutations are predicted to disrupt consensus ETS transcription factor-binding sites and are correlated with both reduced SDHD gene expression and poor prognosis. However, the consequence of these mutations on SDHD expression in melanoma is still unclear. Here, we found that expression of SDHD in melanoma correlated with the expression of multiple ETS transcription factors, particularly in SDHD promoter wild-type samples. Consistent with the predicted loss of ETS transcription factor binding, we observed that recurrent hotspot mutations resulted in decreased luciferase activity in reporter assays. Furthermore, we demonstrated specific GABPA and GABPB1 binding to probes containing the wild-type promoter sequences, with binding disrupted by the SDHD hotspot promoter mutations in both quantitative mass spectrometry and band-shift experiments. Finally, using siRNA-mediated knockdown across multiple melanoma cell lines, we determined that loss of GABPA resulted in reduced SDHD expression at both RNA and protein levels. These data are consistent with a key role for GABPA/B1 as the critical ETS transcription factors deregulating SDHD expression in the context of highly recurrent promoter mutations in melanoma and warrant a detailed search for other recurrent promoter mutations that create or disrupt GABPA consensus sequences. Cancer Res; 77(7); 1649-61. ©2017 AACR.
| S-EPMC6711603 | biostudies-literature
Project description:Cell cycle transitions are often triggered by the proteolysis of key regulatory proteins. In Caulobacter crescentus, the G1-S transition involves the degradation of an essential DNA-binding response regulator, CtrA, by the ClpXP protease. Here, we show that another critical cell cycle regulator, SciP, is also degraded during the G1-S transition, but by the Lon protease. SciP is a small protein that binds directly to CtrA and prevents it from activating target genes during G1. We demonstrate that SciP must be degraded during the G1-S transition so that cells can properly activate CtrA-dependent genes following DNA replication initiation and the reaccumulation of CtrA. These results indicate that like CtrA, SciP levels are tightly regulated during the Caulobacter cell cycle. In addition, we show that formation of a complex between CtrA and SciP at target promoters protects both proteins from their respective proteases. Degradation of either protein thus helps trigger the destruction of the other, facilitating a cooperative disassembly of the complex. Collectively, our results indicate that ClpXP and Lon each degrade an important cell cycle regulator, helping to trigger the onset of S phase and prepare cells for the subsequent programmes of gene expression critical to polar morphogenesis and cell division.
| S-EPMC3596498 | biostudies-literature
Project description:Many non-coding transcripts (ncRNA) generated by RNA polymerase II in S. cerevisiae are terminated by the Nrd1-Nab3-Sen1 complex. However, Sen1 helicase levels are surprisingly low compared with Nrd1 and Nab3, raising questions regarding how ncRNA can be terminated in an efficient and timely manner. We show that Sen1 levels increase during the S and G2 phases of the cell cycle, leading to increased termination activity of NNS. Overexpression of Sen1 or failure to modulate its abundance by ubiquitin-proteasome-mediated degradation greatly decreases cell fitness. Sen1 toxicity is suppressed by mutations in other termination factors, and NET-seq analysis shows that its overexpression leads to a decrease in ncRNA production and altered mRNA termination. We conclude that Sen1 levels are carefully regulated to prevent aberrant termination. We suggest that ncRNA levels and coding gene transcription termination are modulated by Sen1 to fulfill critical cell cycle-specific functions.
| S-EPMC5919780 | biostudies-literature