| First Author | Raafat A | Year | 2017 |
| Journal | Sci Rep | Volume | 7 |
| Issue | 1 | Pages | 13690 |
| PubMed ID | 29057904 | Mgi Jnum | J:255762 |
| Mgi Id | MGI:6109844 | Doi | 10.1038/s41598-017-13989-7 |
| Citation | Raafat A, et al. (2017) The ANK repeats of Notch-4/Int3 activate NF-kappaB canonical pathway in the absence of Rbpj and causes mammary tumorigenesis. Sci Rep 7(1):13690 |
| abstractText | Transgenic mice expressing the Notch-4 intracellular domain (designated Int3) in the mammary gland have two phenotypes exhibited with 100% penetrance: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch-4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. Interestingly, WAP-Int3/Rbpj knockout mice have normal mammary gland development but still developed mammary tumors with a slightly longer latency than the WAP-Int3 mice. Thus, Notch-induced mammary tumor development is Rbpj-independent. Here, we show that Int3 activates NF-kappaB in HC11 cells in absence of Rbpj through an association with the IKK signalosome. Int3 induced the canonical NF-kappaB activity and P50 phosphorylation in HC11 cells without altering the NF-kappaB2 pathway. The minimal domain within the Int3 protein required to activate NF-kappaB consists of the CDC10/Ankyrin (ANK) repeats domain. Treatment of WAP-Int3 tumor bearing mice with an IKK inhibitor resulted in tumor regression. In a soft agar assay, treatment of HC11-Int3 cells with P50-siRNA caused a significant decrease in colony formation. In addition, Wap-Int3/P50 knockout mice did not develop mammary tumors. This data indicates that the activation of NF-kappaB canonical signaling by Notch-4/Int3 is ANK repeats dependent, Rbpj-independent, and is mediated by IKK activation and P50 phosphorylation causing mammary tumorigenesis. |
