Targeting eIF4F Translation Initiation Complex with SBI-756 Sensitizes B Lymphoma Cells to Venetoclax
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ABSTRACT:
PROVIDER: PRJNA670855 | ENA |
REPOSITORIES: ENA
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Project description:Through the study of translation regulation, we identify the disruption of eIF4F assembly as a promising approach to enhance venetoclax efficacy in non-Hodgkin’s lymphoma.
2020-10-25 | GSE159906 | GEO
Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.
2019-05-03 | GSE125403 | GEO
Project description:Targeting mitochondrial structure sensitizes AML to Venetoclax
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| S-EPMC7960756 | biostudies-literature
Project description:We established acquired venetoclax resistant OCI-LY1R cell line by treating venetoclax sensitive parental OCI-Ly1 cell line with increasing doses of venetoclax up till 1µM. Parental OCI-Ly1 and venetoiclax-resistant OCI-Ly1R cells were treated with vehicle control or decitabine at 1uM for 3 days. We found that decitabine differantially regulated gene expression in venetoclax sensitive and resistant cells. With gene set enrichment analysis, we identified two pathways that were deregulated by decitabine in both cell lines.
2023-07-25 | GSE223598 | GEO
Project description:The emergence of effective inhibitors for BRAF-mutant melanoma has had major impact on clinical management of melanoma 1,2. The initial success of such treatments, however, has been limited due to the propensity of melanomas to develop resistance 3-5. In most cases, mechanisms underlying BRAFi-resistance include activation of genetic or epigenetic pathways that circumvent targeted BRAF and restore MAPK and related signaling to levels sufficient to encourage tumorigenesis 3-7. This outcome has led to development of combination therapies targeting both BRAF and associated pathways, such as MEK and PI3K 8,9, albeit, with limited success. Furthermore, 50% of melanomas, such as those harboring NRAS and NF1 mutations, lack BRAF mutations and are thus not amenable to BRAFi therapy 10,11. Thus tumor chemoresistance and the lack of therapies for BRAF wild-type (WT) tumors remains a major clinical challenge. Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex has been an appealing strategy to potentiate effectiveness of existing cancer therapies. We identify that the small molecule SBI-0640756 (SBI-756) binds to eIF4G1 and dissociates it from eIF4E, leading to disruption of the eIF4F complex. SBI-756 treatment also inhibited AKT, NF-κB and mTOR signaling. We detected the melanoma cell lines have different response to SBI-756. It important to invertigate genes and pathways in melanoma cells resistant to SBI-756.
2016-05-01 | GSE66401 | GEO
Project description:Translation is initiated by binding of the eIF4F complex to the 5' cap of the mRNA, which is followed by scanning of the initiation codon by scanning ribosomes. Here we demonstrate that the ASC-1 complex (ASCC), which was previously shown to promote the dissociation of colliding 80S ribosomes, associates with the scanning ribosomes to regulate translation initiation. Sel-TCP-seq analysis revealed that ASCC3, a subunit of ASCC with a helicase domain, localizes predominantly to the 5' untranslated region of mRNAs. Knockdown of ASCC3 resulted in reduced translation efficiency associated with reduced 43S preinitiation complex (PIC) loading and a reduced speed of scanning ribosomes. In addition, depletion of the ubiquitin ligase ZNF598, a sensor of collided 80S ribosomes, also reduces the PIC loading and speed of scanning ribosomes. Our results have thus revealed that ASCC is required not only for dissociation of colliding 80S ribosomes, but also for efficient translation initiation by scanning ribosomes.
2023-03-31 | GSE186502 | GEO
Project description:Epstein-Barr virus (EBV) expresses several mRNAs produced from intronless genes that could be unfavorably translated in front of cellular spliced mRNAs. To overpass these limitations, the virus encodes a RNA-binding protein (RBP), EB2, which is already known to facilitate nuclear mRNAs export and to increase their translational yield. Here we show that EB2 binds both nuclear and cytoplasmic cap-binding complexes (respectively, CBC and eIF4F), and the poly(A)-binding protein (PABP) to enhance translation initiation of a given mRNP. Interestingly, such effect can be obtained only if EB2 was initially bound to the native mRNPs in the nucleus. We also demonstrate that the EB2-eIF4F-PABP association renders the translation of these mRNPs less sensitive to inhibitors of initiation. Taken together, our new data suggest that EB2 binds and stabilizes cap-binding complexes to increase mRNP translation and demonstrate the importance of the mRNP assembly process in the nucleus to promote translation in the cytoplasm.
2022-03-03 | PXD003800 | Pride
Project description:One of the most regulated steps of translation initiation is the recruitment of an mRNA by the translation machinery. In eukaryotes, this step is mediated by the 5M-BM-4end cap-binding factor eIF4E bound to the bridge protein eIF4G and forming the eIF4F complex. In plants, different isoforms of eIF4E and eIF4G form the antigenically distinct eIF4F and eIF(iso)4F complexes proposed to mediate selective translation. Using a microarray analysis of polyribosome- and non-polyribosome-purified mRNAs from 15 day-old Arabidopsis thaliana wild type [WT] and eIF(iso)4E knockout mutant [AteIF(iso)4E-1] seedlings we found 79 transcripts shifted from polyribosomes toward non-polyribosomes, and 47 mRNAs with the opposite behavior in the mutant. The translationally decreased mRNAs were overrepresented in root-preferentially expressed genes and proteins from the endomembrane system, including several transporters such as the phosphate transporter PHOSPHATE1 (PHO1), Sucrose transporter 3 (SUC3), the ABC transporter-like with ATPase activity (MRP11) and five electron transporters, as well as signal transduction-, protein modification- and transcription-related proteins. For transcriptional analysis used total RNA of AteIF(iso)4E-1 seedlings of 15 days old to known the changes on transcripts leves by the eIF(iso)4E absence, using as control Wt seedlings. The experiments were performed in duplicate, and swap analysis were done. For translational analysis, used non-polysomal and polysomal RNA of AteIF(iso)4E-1 seedlings of 15 days old in order to known the transcripts that are modified in their translational levels by the eIF(iso)4E absence, using as control non polysomal and polysomal RNA of Wt seddlings.
2013-07-26 | E-GEOD-29386 | biostudies-arrayexpress