Retinoid-induced activation of NF-kappaB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells
In: Oncogene, Jg. 24 (2005-07-27), Heft 48
Online
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Zugriff:
All-trans retinoic acid (ATRA) significantly improves the survival of patients with acute promyelocytic leukemia (APL) by inducing granulocytic differentiation of leukemia cells. Since an activation of the transcription factor NF-kappaB occurs during ATRA-induced maturation of APL cells, a mechanistic link between these two processes was investigated. Using an in vitro model for APL, we report that ectopic overexpression of a repressor of NF-kappaB activation did not affect granulocytic differentiation. Importantly, NF-kappaB inhibition markedly resulted in a decreased viability of the differentiated cells, which correlated with increased apoptosis. Apoptosis was accompanied by a sustained activation of the c-Jun N-terminal kinase (JNK). Inhibition of JNK by the specific inhibitor SP600125 or by transfection of a dominant-negative mutant of JNK1 reduced the percentage of apoptotic cells, thus showing that JNK activation constitutes a death signal. Furthermore, impairment of NF-kappaB activation resulted in increased levels of reactive oxygen species (ROS) upon ATRA treatment. ROS accumulation was suppressed by the antioxidant butylated hydroxyanisol, which also abolished ATRA-induced JNK activation and apoptosis. Altogether, our results demonstrate an anti-apoptotic effect of NF-kappaB activation during ATRA-induced differentiation of NB4 cells and identify repression of ROS-mediated JNK activation as a mechanism for this effect. Our observations also suggest that NF-kappaB signalling may contribute to an accumulation of mature APL cells and participate in the development of ATRA syndrome.
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Retinoid-induced activation of NF-kappaB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells
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Autor/in / Beteiligte Person: | Mathieu, Julie ; Besançon, Françoise ; Lanotte, Michel ; Giraudier, Stéphane |
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Zeitschrift: | Oncogene, Jg. 24 (2005-07-27), Heft 48 |
Veröffentlichung: | 2005 |
Medientyp: | unknown |
ISSN: | 0950-9232 (print) |
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