Notch Secretase

The Notch-γ-Secretase Pathway

Notch activation involves the proteolytic cleavage of the Notch ligand/receptor complex by γ-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 γ-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 γ-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.

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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).