Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Ortega, M; Bhatnagar, H; Lin, AP; Wang, L; Aster, JC; Sill, H; Aguiar, RC.
A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies.
Leukemia. 2015; 29(4):968-976
Doi: 10.1038/leu.2014.302
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Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Sill Heinz
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- Abstract:
- Growing evidence suggests that microRNAs (miRNAs) facilitate the cross-talk between transcriptional modules and signal transduction pathways. MYC and NOTCH1 contribute to the pathogenesis of lymphoid malignancies. NOTCH induces MYC, connecting two signaling programs that enhance oncogenicity. Here we show that this relationship is bidirectional and that MYC, via a miRNA intermediary, modulates NOTCH. MicroRNA-30a (miR-30a), a member of a family of miRNAs that are transcriptionally suppressed by MYC, directly binds to and inhibits NOTCH1 and NOTCH2 expression. Using a murine model and genetically modified human cell lines, we confirmed that miR-30a influences NOTCH expression in a MYC-dependent fashion. In turn, through genetic modulation, we demonstrated that intracellular NOTCH1 and NOTCH2, by inducing MYC, suppressed miR-30a. Conversely, pharmacological inhibition of NOTCH decreased MYC expression and ultimately de-repressed miR-30a. Examination of genetic models of gain and loss of miR-30a in diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) cells suggested a tumor-suppressive role for this miRNA. Finally, the activity of the miR-30a-NOTCH-MYC loop was validated in primary DLBCL and T-ALL samples. These data define the presence of a miRNA-mediated regulatory circuitry that may modulate the oncogenic signals originating from NOTCH and MYC.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- B-Lymphocytes - metabolism
- B-Lymphocytes - pathology
- Gene Expression Regulation, Neoplastic -
- Genes, Reporter -
- Humans -
- Luciferases - genetics
- Luciferases - metabolism
- Lymphoma, Large B-Cell, Diffuse - genetics
- Lymphoma, Large B-Cell, Diffuse - metabolism
- Lymphoma, Large B-Cell, Diffuse - pathology
- Male -
- Mice -
- Mice, Inbred C57BL -
- Mice, Transgenic -
- MicroRNAs - genetics
- MicroRNAs - metabolism
- Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
- Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism
- Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology
- Primary Cell Culture -
- Proto-Oncogene Proteins c-myc - genetics
- Proto-Oncogene Proteins c-myc - metabolism
- Receptor, Notch1 - genetics
- Receptor, Notch1 - metabolism
- Receptor, Notch2 - genetics
- Receptor, Notch2 - metabolism
- Signal Transduction -
- T-Lymphocytes - metabolism
- T-Lymphocytes - pathology