The Notch ligand, Delta-1, reduces TNF-alpha-induced growth suppression and apoptosis by decreasing activation of caspases in U937 cells.
The Notch signaling pathway plays an important role in the regulation of self-renewal and differentiation of hematopoietic progenitors. Tumor necrosis factor (TNF)-alpha induces apoptosis through activation of caspase pathway. A monoblastic leukemia cell line, U937, undergoes apoptosis following stimulation with TNF-alpha. We found that Notch activation induced by a recombinant Notch ligand, Delta-1, reduced the TNF-alpha-induced growth suppression and apoptosis in U937 cells. As the molecular mechanism involved, we showed Delta-1 stimulation partially suppressed the sequential activation of caspase-8, caspase-3, and, PARP induced by TNF-alpha. The TNF-alpha-induced activation of c-Jun N-terminal kinase (JNK), p38, and NF-kappaB was not affected by Delta-1 stimulation. The cells needed to be exposed to Delta-1 prior to TNF-alpha stimulation to reduce the suppressive effect of TNF-alpha. Therefore, we thought that Delta-1 stimulation might reduce the expression of TNF-receptor (R) 1 and proteins to modulate the activation of caspases such as FLIP and XIAP. However, Delta-1 stimulation did not affect their expression. The precise mechanism by which Notch signaling suppresses caspase activation has yet to be determined. This is the first report to show the relationship between Notch activation and TNF-R1 signaling. The findings suggest possible mechanisms by which Notch activation supports cell survival.
Murata-Ohsawa
Mai
M
Department of Laboratory Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo 113-8519, Japan.
Tohda
Shuji
S
Kogoshi
Hanae
H
Nara
Nobuo
N
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D018121:Receptors, Cytokine / Q000502:physiology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D020298:U937 Cells
C498762:CRLF2 protein, human; D018121:Receptors, Cytokine; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases