Notch-1 regulates cell death independently of differentiation in murine erythroleukemia cells through multiple apoptosis and cell cycle pathways

✍ Scribed by Mei-Shiang Jang; Haixi Miao; Nadia Carlesso; Leslie Shelly; Andrei Zlobin; Nicole Darack; Jian-Zhong Qin; Brian J. Nickoloff; Lucio Miele

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 518 KB
• Volume: 199
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.10467

✦ Synopsis

Abstract

Notch signaling is a potential therapeutic target for various solid and hematopoietic malignancies. We have recently shown that downregulation of Notch‐1 expression has significant anti‐neoplastic activity in pre‐clinical models. However, the mechanisms through which Notch modulation may affect cell fate in cancer remain poorly understood. We had previously shown that Notch‐1 prevents apoptosis and is necessary for pharmacologically induced differentiation in murine erythroleukemia (MEL) cells. We investigated the mechanisms of these effects using three experimental strategies: (1) MEL cells stably transfected with antisense Notch‐1 or constitutively active Notch‐1, (2) activation of Notch‐1 by a cell‐associated ligand, and (d3) activation of Notch‐1 by a soluble peptide ligand. We show that: (1) downregulation of Notch‐1 sensitizes MEL cells to apoptosis induced by a Ca^2+^ influx or anti‐neoplastic drugs; (2) Notch‐1 downregulation induces phosphorylation of c‐Jun N‐terminal kinase (JNK) while constitutive activation of Notch‐1 or prolonged exposure to a soluble Notch ligand abolishes it; (3) Notch‐1 has dose‐ and time‐dependent effects on the levels of apoptotic inhibitor Bcl‐x~L~ and cell cycle regulators p21^cip1/waf1^, p27^kip1^, and Rb; and (4) Notch‐1 activation by a cell‐associated ligand is accompanied by rapid and transient induction of NF‐κB DNA‐binding activity. The relative effects of Notch‐1 signaling on these pathways depend on the levels of Notch‐1 expression, the mechanism of activation, and the timing of activation. The relevance of these findings to the role of Notch signaling in differentiation and cancer are discussed. © 2003 Wiley‐Liss, Inc.