The Notch--Secretase Pathway
The Notch--Secretase Pathway
Notch activation involves the proteolytic cleavage of the Notch ligand/receptor complex by -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 -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 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.
References
1. O'Neil, J., et al., FBW7 mutations in leukemic cells mediate NOTCH pathway activation and
resistance to -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).