This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined.
Onkogen
Notch3 is expressed in human lung tumors. Inhibition of the Notch3 pathway in lung cancer cells reduces growth in soft agar [1].
Transgenic mice were generated in which expression of the Notch3 intracellular domain was driven by the proximal lck promoter. After 6–8 weeks, highly aggressive Notch3-positive T-cell lymphomas dominated the spleen and lymph nodes of multiple transgenic mice lines [2].
Retrovirus expressing the intracellular domain of Notch3 were injected into mouse forebrain ventricles at embryonic day 9.5. Within several weeks of birth, choroid plexus tumors (CPTs) formed in the 4th ventricle of the injected mice. Animals injected with a control retrovirus did not develop tumors[3].
Notch3-/- mice are viable, fertile, and develop normally [4,5]
A breast cancer cell line (MDA-MB231) expressing Notch3 showed reduction of colony formation in soft-agar assays. MMTV-Neu mice, a model of mammary gland tumor, was crossed with Notch3 loss-of-function mice. Loss of Notch3 induced a significant reduction of tumor-free survival [6].
Es ist nicht gezeigt, dass der Funktionsverlust des Gens zur Entstehung von Tumoren führt.
[1] Haruki, N. et al., Cancer Res, 2005, 65 (9), 3555–3561. doi: 10.1158/0008-5472.CAN-04-3132.
[2] Bellavia, D. et al., EMBO J, 2000, 19 (13), 3337–3348. doi: 10.1093/emboj/19.13.3337.
[3] Dang, L. et al., Oncogene, 2006, 25 (3), 487–491. doi: 10.1038/sj.onc.1209074.
[4] Kitamoto, T. et al., Biochemical and Biophysical Research Communications, 2005, 331 (4), 1154–1162. doi: 10.1016/j.bbrc.2005.03.241.
[5] Krebs, L. T. et al., Genesis, 2003, 37 (3), 139–143. doi: 10.1002/gene.10241.
[6] Brahim, S. et al., Cell Death Dis, 2023, 14 (2). doi: 10.1038/s41419-023-05674-7.
