ArticleOpen biology2014
A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1.
Article in Open biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 24 citations in OpenAlex.
- Targeting Cancer Translational Plasticity: IRES-Driven Metabolism and Survival Within the Tumor Microenvironment.Cancers · 2025Review
- Masitinib Inhibits Hepatitis A Virus Replication.International journal of molecular sciences · 2023Article
- Translational and post-translational control of human naïve versus primed pluripotency.iScience · 2022Article
- Article
- Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition.Scientific reports · 2021Article
- Review
- So close, no matter how far: multiple paths connecting transcription to mRNA translation in eukaryotes.EMBO reports · 2020Review
- Targeting RNA helicases in cancer: The translation trap.Biochimica et biophysica acta. Reviews on cancer · 2017Review
- More than just scanning: the importance of cap-independent mRNA translation initiation for cellular stress response and cancer.Cellular and molecular life sciences : CMLS · 2017Review
- Glucagon and Insulin Cooperatively Stimulate Fibroblast Growth Factor 21 Gene Transcription by Increasing the Expression of Activating Transcription Factor 4.The Journal of biological chemistry · 2017Article
- Review
- Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer.The Journal of experimental medicine · 2016Article
- An miRNA-mediated therapy for SCA6 blocks IRES-driven translation of the CACNA1A second cistron.Science translational medicine · 2016Article
- The amyloid precursor protein (APP) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism.Neurobiology of aging · 2015Article
- Characterization of LEF1 High Expression and Novel Mutations in Adult Acute Lymphoblastic Leukemia.PloS one · 2015Article
- Cap-Independent Translation in Hematological Malignancies.Frontiers in oncology · 2015Review
- Hippuristanol - A potent steroid inhibitor of eukaryotic initiation factor 4A.Translation (Austin, Tex.)Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Internal ribosome entry sites (IRESs) in cellular mRNAs direct expression of growth-promoting factors through an alternative translation mechanism that has yet to be fully defined. Lymphoid enhancer factor-1 (LEF-1), a Wnt-mediating transcription factor important for cell survival and metastasis in cancer, is produced via IRES-directed translation, and its mRNA is frequently upregulated in malignancies, including chronic myeloid leukaemia (CML). In this study, we determined that LEF1 expression is regulated by Bcr-Abl, the oncogenic protein that drives haematopoietic cell transformation to CML. We have previously shown that the LEF1 5' untranslated region recruits a complex of proteins to its IRES, including the translation initiation factor eIF4A. In this report, we use two small molecule inhibitors, PP242 (dual mTOR (mammalian target of rapamycin) kinase inhibitor) and hippuristanol (eIF4A inhibitor), to define IRES regulation via a Bcr-Abl-mTOR-eIF4A axis in CML cell lines and primary patient leukaemias. We found that LEF1 and other IRESs are uniquely sensitive to the activities of Bcr-Abl/mTOR. Most notably, we discovered that eIF4A, an RNA helicase, elicits potent non-canonical effects on the LEF1 IRES. Hippuristanol inhibition of eIF4A stalls translation of IRES mRNA and triggers dissociation from polyribosomes. We propose that a combination drug strategy which targets mTOR and IRES-driven translation disrupts key factors that contribute to growth and proliferation in CML.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.