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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.
Oncogene. 2005 Nov 03; 24(48):7145-55.O

Abstract

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.

Authors+Show Affiliations

INSERM U685, Centre Hayem, Hôpital St Louis, 1 avenue Claude Vellefaux, 75475 Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16044154

Citation

Mathieu, Julie, et al. "Retinoid-induced Activation of NF-kappaB in APL Cells Is Not Essential for Granulocytic Differentiation, but Prolongs the Life Span of Mature Cells." Oncogene, vol. 24, no. 48, 2005, pp. 7145-55.
Mathieu J, Giraudier S, Lanotte M, et al. Retinoid-induced activation of NF-kappaB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells. Oncogene. 2005;24(48):7145-55.
Mathieu, J., Giraudier, S., Lanotte, M., & Besançon, F. (2005). Retinoid-induced activation of NF-kappaB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells. Oncogene, 24(48), 7145-55.
Mathieu J, et al. Retinoid-induced Activation of NF-kappaB in APL Cells Is Not Essential for Granulocytic Differentiation, but Prolongs the Life Span of Mature Cells. Oncogene. 2005 Nov 3;24(48):7145-55. PubMed PMID: 16044154.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Retinoid-induced activation of NF-kappaB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells. AU - Mathieu,Julie, AU - Giraudier,Stéphane, AU - Lanotte,Michel, AU - Besançon,Françoise, PY - 2005/7/27/pubmed PY - 2005/12/13/medline PY - 2005/7/27/entrez SP - 7145 EP - 55 JF - Oncogene JO - Oncogene VL - 24 IS - 48 N2 - 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. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/16044154/Retinoid_induced_activation_of_NF_kappaB_in_APL_cells_is_not_essential_for_granulocytic_differentiation_but_prolongs_the_life_span_of_mature_cells_ L2 - https://doi.org/10.1038/sj.onc.1208889 DB - PRIME DP - Unbound Medicine ER -