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

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-kappaB 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.

Jang MS ，Miao H ，Carlesso N ，Shelly L ，Zlobin A ，Darack N ，Qin JZ ，Nickoloff BJ ，Miele L ... -  《JOURNAL OF CELLULAR PHYSIOLOGY》

Modulation of vascular smooth muscle cell growth by magnesium-role of mitogen-activated protein kinases.

Touyz RM ，Yao G 《JOURNAL OF CELLULAR PHYSIOLOGY》

Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis.

Qi R ，An H ，Yu Y ，Zhang M ，Liu S ，Xu H ，Guo Z ，Cheng T ，Cao X ... -  《CANCER RESEARCH》

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-beta(1)-dependent pathway.

Jiang XH ，Lam SK ，Lin MC ，Jiang SH ，Kung HF ，Slosberg ED ，Soh JW ，Weinstein IB ，Wong BC ... -  《ONCOGENE》

A new molecular role for iron in regulation of cell cycling and differentiation of HL-60 human leukemia cells: iron is required for transcription of p21(WAF1/CIP1) in cells induced by phorbol myristate acetate.

Gazitt Y ，Reddy SV ，Alcantara O ，Yang J ，Boldt DH ... -  《JOURNAL OF CELLULAR PHYSIOLOGY》