| First Author | Fragoso R | Year | 2012 |
| Journal | PLoS Genet | Volume | 8 |
| Issue | 8 | Pages | e1002855 |
| PubMed ID | 22916024 | Mgi Jnum | J:188125 |
| Mgi Id | MGI:5439209 | Doi | 10.1371/journal.pgen.1002855 |
| Citation | Fragoso R, et al. (2012) Modulating the strength and threshold of NOTCH oncogenic signals by mir-181a-1/b-1. PLoS Genet 8(8):e1002855 |
| abstractText | Oncogenes, which are essential for tumor initiation, development, and maintenance, are valuable targets for cancer therapy. However, it remains a challenge to effectively inhibit oncogene activity by targeting their downstream pathways without causing significant toxicity to normal tissues. Here we show that deletion of mir-181a-1/b-1 expression inhibits the development of Notch1 oncogene-induced T cell acute lymphoblastic leukemia (T-ALL). mir-181a-1/b-1 controls the strength and threshold of Notch activity in tumorigenesis in part by dampening multiple negative feedback regulators downstream of NOTCH and pre-T cell receptor (TCR) signaling pathways. Importantly, although Notch oncogenes utilize normal thymic progenitor cell genetic programs for tumor transformation, comparative analyses of mir-181a-1/b-1 function in normal thymocyte and tumor development demonstrate that mir-181a-1/b-1 can be specifically targeted to inhibit tumor development with little toxicity to normal development. Finally, we demonstrate that mir-181a-1/b-1, but not mir-181a-2b-2 and mir-181-c/d, controls the development of normal thymic T cells and leukemia cells. Together, these results illustrate that NOTCH oncogene activity in tumor development can be selectively inhibited by targeting the molecular networks controlled by mir-181a-1/b-1. |
