The Notch- -Secretase Pathway

1. The Notch--Secretase Pathway

2. The Notch--Secretase Pathway Notch activation involves the proteolytic cleavage of the Notch ligand/receptor complex by g-secretase to release the Notch intracellular domain fragment (NICD) that translocates to the nucleus and upregulates expression of Myc, Hes1, and other genes.1 When the DAOY medulloblastoma cell line was transfected with NICD2 to make Notch signaling constitutively active, the transfected cells produced more xenograft tumors than the non-transformed DAOY cells and increased the population of both CD133+ and side population stem-like cells in culture. In contrast, inhibition of g-secretase reduced the side population to 0.01% of the total cell count and inhibited by 90% the ability of cells to colonize soft agar or to form tumor xenografts in immune-compromised mice. NICD2 transfection protected the cells from the effects of g-secretase inhibition.2 Thus, in some tumor types, the inhibition of Notch signaling can deplete a population of cells that are required for tumor initiation.

3. References 1. O'Neil, J., et al., FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to g-secretase inhibitors. J. Exp. Med., 204, 1813-1824 (2007). 2. Fan, X., et al., Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res., 66, 7445-7452 (2006).