Notch-1 inhibits apoptosis in murine erythroleukemia cells and is necessary for differentiation induced by hybrid polar compounds

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Abstract
Strikingly increased expression of notch‐1 has been demonstrated in several human malignancies and pre‐neoplastic lesions. However, the functional consequences of notch‐1 overexpression in transformed cells remain unclear. We investigated whether endogenously expressed notch‐1 controls cell fate determination in mouse erythroleukemia (MEL) cells during pharmacologically induced differentiation. We found that notch‐1 expression is modulated during MEL cell differentiation. Premature downregulation of notch‐1 during differentiation, by antisense S‐oligonucleotides or by enforced expression of antisense notch‐1 mRNA, causes MEL cells to abort the differentiation program and undergo apoptosis. Downregulation of notch‐1 expression in the absence of differentiation inducer increases the likelihood of spontaneous apoptosis. We conclude that in MEL cells, endogenous notch‐1 expression controls the apoptotic threshold during differentiation and growth. In these cells, notch‐1 allows differentiation by preventing apoptosis of pre‐committed cells. This novel function of notch‐1 may play a role in regulating apoptosis susceptibility in notch‐1 expressing tumor cells. J. Cell. Biochem. 73:164–175, 1999.