Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA266430 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The c-MYC onco-protein regulates a large array of genes playing an important role in basic cell functions. Because of its central role in growth regulation, c-MYC expression must be tightly regulated. The NHEIII1 located upstream of the P1 promoter regulates up to 80% of c-MYC transcription, and includes a C/G rich region (Pu27) which forms a G-quadruplex structure. We have identified seventeen genomic G-quadruplex-forming motifs which have more than 90% identity with Pu27 found on different chromosomes throughout the human genome. Of thirteen members of the Pu27 family tested, all interact specifically with NHEIII1 sequence and inhibit leukemic cells proliferation to differing degrees. Further characterization of three Pu27 homologous sequences (Pu5-, Pu9- and Pu27) reveals a dose/time dependent response on growth inhibition in four leukemia cell lines and down regulation of c-MYC at RNA and protein level. The three Pu27 family members selectively alter expression of genes involved in cell cycle progression/regulation, DNA damage/repair and histone modification. In conclusion, we have identified sixteen genomic G-quadruplex-forming sequences homologous to Pu27 of c-MYC promoter sharing the same structure and function. It is likely that these sequences play important biologic roles in c-MYC regulation and provide an ideal tool for targeted cancer therapy.
2017-12-01 | GSE63016 | GEO
Project description:Expression data by G-quadruplex (G4) forming oligonucleotides transfection in 3D culture.
| PRJNA242680 | ENA
Project description:The MYC transcription factor is a master regulator of diverse cancer pathways and somatic cell reprogramming. MYC is a compelling therapeutic target that exhibits cancer-specific cellular effects. Pharmacologic inhibition of MYC function has proven challenging due to its numerous modes of forced expression and the difficulty of disrupting protein-DNA interactions. Here we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule bromodomain inhibitors of the BET family of chromatin adaptors. This transcriptional suppression of MYC was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from growth suppression by BET inhibitors and revealed that MYC exerts a direct and tight control of key pro-growth and anti-apoptotic target genes. Transcriptional profiling of two cells after 4 and 8 hours of treatment with BET inhibitor shows that both MYC and its targets are strongly down-regulated. We thus demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains, and suggest that such inhibitors may have broad clinical applicability given the widespread pathogenetic role of MYC in cancer. LP-1, a multiple myeloma cell line, and Raji, a Burkitt lymphoma cell line, were treated with BET inhibitor and an inactive enantiomer for 4 or 8 hours. Two biological replicates of each sample were profiled on exon arrays.
2011-09-18 | E-GEOD-29449 | biostudies-arrayexpress
Project description:The MYC transcription factor is a master regulator of diverse cancer pathways and somatic cell reprogramming. MYC is a compelling therapeutic target that exhibits cancer-specific cellular effects. Pharmacologic inhibition of MYC function has proven challenging due to its numerous modes of forced expression and the difficulty of disrupting protein-DNA interactions. Here we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule bromodomain inhibitors of the BET family of chromatin adaptors. This transcriptional suppression of MYC was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from growth suppression by BET inhibitors and revealed that MYC exerts a direct and tight control of key pro-growth and anti-apoptotic target genes. Transcriptional profiling of two cells after 4 and 8 hours of treatment with BET inhibitor shows that both MYC and its targets are strongly down-regulated. We thus demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains, and suggest that such inhibitors may have broad clinical applicability given the widespread pathogenetic role of MYC in cancer.
2011-09-19 | GSE29449 | GEO
Project description:KIT mutant acute myeloid leukemia (AML) confers a worse prognosis for patients in a subtype of AML that has an otherwise favorable outcome. Here, we demonstrate that lysine specific demethylase 1 (LSD1) inhibition potentiates cytotoxic effect of KIT inhibition in KIT mutant AML. We identified loss of PU.1 binding to be a key feature of LSD1 inhibition, contributing to a decrease in MYC enhancer and promoter activation. This loss of MYC enhancer/promoter activation results in decreased MYC expression and binding at proliferation associated promoters decreasing cell cycle progression. Our results nominate PI3K/AKT pathway inactivation as a key feature of KIT and LSD1 inhibition ultimately leading to decreased MYC and blocking LSD1 from activating its targets. Our findings support a mechanistic model for synergy between dual KIT and LSD1 inhibition and suggest this combination should be investigated in a clinical setting.
2022-05-29 | GSE182150 | GEO
Project description:It is generally thought that splicing factors regulate alternative splicing through binding to RNA consensus sequences. In addition to these linear motifs, RNA secondary structure is emerging as an important layer in splicing regulation. Here we demonstrate that RNA elements with G-quadruplex forming capacity promote exon inclusion. Destroying G-quadruplex forming capacity while keeping G-tracts intact abrogates exon inclusion. Analysis of RNA binding protein footprints revealed that G-quadruplexes are enriched in hnRNPF-binding sites and near hnRNPF-regulated alternatively spliced exons in the human transcriptome. Moreover, hnRNPF regulates an EMT-associated CD44 isoform switch in a G-quadruplex-dependent manner, which results in inhibition of EMT. Mining breast cancer TCGA datasets, we demonstrate that hnRNPF negatively correlates with an EMT gene signature and positively correlates with patient survival. These data suggest a critical role for RNA G-quadruplexes in regulating alternative splicing. Modulation of G-quadruplex structural integrity may control cellular processes important for tumor progression.
2018-01-22 | GSE107542 | GEO
Project description:In this study we discover proteins that bind to G4 quadruplex DNA structure. We use modified c-myc quadruplex as a bait, and compare it to the control bait - T15 oligo. We use spectral counts and G-test to determine significant binders. T15 and G4 datafiles are uploaded
2016-07-07 | PXD003501 | Pride
Project description:YY1 is involved in homologous recombination inhibition at guanine quadruplex sites in human cells
| PRJNA1072123 | ENA
Project description:Acute Myeloid Leukemia (AML) is the most common and aggressive form of acute leukemia, with a 5-year survival rate of just 24%. Over a third of all AML patients harbor activating mutations in kinases, such as the receptor tyrosine kinases FLT3 and KIT. FLT3 and KIT mutations are associated with poor clinical outcomes and lower remission rates in response to standard-of-care chemotherapy. We have recently identified that the core kinase of the non-homologous end joining DNA repair pathway, DNA-PK, is activated downstream of FLT3; and targeting DNA-PK sensitized FLT3-mutant AML cells to standard-of-care therapies. Herein, we investigated DNA-PK as a possible therapeutic vulnerability in KIT mutant AML, using isogenic FDC-P1 myeloid progenitor cell lines transduced with an empty vector or oncogenic mutant KIT (V560G, D816V). Targeted quantitative phosphoproteomic profiling identified phosphorylation of DNA-PK at threonine 2599 in KIT mutant cells, indicative of DNA-PK activation. Accordingly, proliferation assays revealed that KIT mutant FDC-P1 cells were more sensitive to the DNA-PK inhibitors M3814 or NU7441, compared to empty vector controls. DNA-PK inhibition combined with inhibition of KIT signaling via using the kinase inhibitors dasatinib or ibrutinib, or the protein phosphatase 2A activators FTY720 or AAL(S), led to synergistic cell death. Discovery phosphoproteomic analysis of KIT-D816V cells revealed that dasatinib single-agent treatment inhibited ERK1 activity, and M3814 single-agent treatment inhibited Akt/mTOR activity. The combination of dasatinib and M3814 treatment inhibited both ERK/MAPK and Akt/mTOR activity, and induced synergistic inhibition of phosphorylation of transcription regulators including MYC and MYB. This study provides insight into the oncogenic pathways regulated by DNA-PK beyond its canonical role in DNA repair, and demonstrates that DNA-PK is a promising novel therapeutic target for KIT mutant cancers.
2023-01-26 | PXD030214 | panorama