| First Author | Liu J | Year | 2014 |
| Journal | Int J Oncol | Volume | 45 |
| Issue | 5 | Pages | 1997-2004 |
| PubMed ID | 25175815 | Mgi Jnum | J:232150 |
| Mgi Id | MGI:5776104 | Doi | 10.3892/ijo.2014.2626 |
| Citation | Liu J, et al. (2014) Postnatal Notch1 activation induces Tcell malignancy in conditional and inducible mouse models. Int J Oncol 45(5):1997-2004 |
| abstractText | The Notch1 signaling pathway is essential for hematopoietic development. However, the effects of postnatal activation of Notch1 signaling on hematopoietic system is not yet fully understood. We previously generated ZEGICNotch1 transgenic mice that have a floxed betageo/stop signal between a CMV promoter and intracellular domain of Notch1 (ICNotch1). Constitutively active ICNotch1 is silent until the introduction of Cre recombinase. In this study, endothelial/hematopoietic specific expression of ICNotch1 in double transgenic ZEGICNotch1/Tie2Cre embryos induced embryonic lethality at E9.5 with defects in vascular system but not in hematopoietic system. Inducible ICNotch1 expression in adult mice was achieved by using tetracycline regulated Cre system. The ZEGICNotch1/Tie2tTA/tetOCre triple transgenic mice survived embryonic development when maintained on tetracycline. Postnatal withdrawal of tetracycline induced expression of ICNotch1 transgene in hematopoietic cells of adult mice. The triple transgenic mice displayed extensive Tcell infiltration in multiple organs and Tcell malignancy of lymph nodes. In addition, the protein levels of p53 and alternative reading frame (ARF) were decreased in lymphomalike neoplasms from the triple transgenic mice while their mRNA expression remained unchanged, suggesting that ICNotch1 might repress ARFp53 pathway by a posttranscriptional mechanism. This study demonstrated that activation of constitutive Notch1 signaling after embryonic development alters adult hematopoiesis and induces Tcell malignancy. |
