NF-κB inhibition sensitizes to starvation-induced cell death in high-risk myelodysplastic syndrome and acute myeloid leukemia

Fabre, Claire; Carvalho, Gabrielle; Tasdemir, Ezgi; Braun, Thorsten; Adès, Lionel; Grosjean, Jérôme; Boehrer, Simone; Métivier, Didier; Souquère, Sylvie; Pierron, Gérard; Fenaux, Pierre; Kroemer, Guido

doi:10.1038/sj.onc.1210187

Cited by 88 publications

(64 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relationship between NF-B signaling and autophagy regulation seems puzzling. Indeed, NF-B has emerged as a negative regulator of autophagy as induced by tumor necrosis factor alpha (TNF-␣), reactive oxygen species, and starvation in some cell lines (16,18). On the other hand, a number of indirect pieces of evidence suggest an activating role for NF-B in autophagy.…”

mentioning

confidence: 99%

p65/RelA Modulates BECN1 Transcription and Autophagy

Copetti

Bertoli

Dalla

et al. 2009

Molecular and Cellular Biology

239

179

View full text Add to dashboard Cite

Recently, autophagy has emerged as a critical process in the control of T-cell homeostasis. Given the pivotal role of NF-B in the signaling events of T cells, we have analyzed and unveiled a conserved NF-B binding site in the promoter of the murine and human BECN1 autophagic gene (Atg6). Accordingly, we demonstrate that the NF-B family member p65/RelA upregulates BECN1 mRNA and protein levels in different cellular systems. Moreover, p65-mediated upregulation of BECN1 is coupled to increased autophagy. The newly identified B site in the BECN1 promoter specifically interacts with p65 both in vitro and in living Jurkat cells upon phorbol myristate acetate (PMA)-ionomycin stimulation, where p65 induction is coupled to BECN1 upregulation and autophagy induction. Finally, anti-CD3-and PMA-ionomycin-mediated activation of T-cell receptor signaling in peripheral T cells from lymph nodes of healthy mice results in an upregulation of BECN1 expression that can be blocked by the NF-B inhibitor BAY 11-7082. Altogether, these data suggest that autophagy could represent a novel route modulated by p65 to regulate cell survival and control T-cell homeostasis.Normal cellular development and growth depend on a finely tuned balance between protein synthesis and degradation. Eukaryotic cells exploit two major routes for protein degradation: autophagy and the ubiquitin-proteasome system. Autophagy is a highly conserved catabolic process whereby long-lived proteins and organelles are engulfed in double-membrane structures called autophagosomes and targeted to the lysosome for degradation and ATP production (33). Autophagy was first characterized in yeast as a process used by cells to survive metabolic stress (59). Many of the autophagic executor genes (ATGs) have been discovered in yeast, and recently a number of mammalian orthologues have been identified. At the molecular level, the autophagic pathway is well conserved and requires several proteins acting in concert at different stages for proper autophagosome formation. During the first steps of autophagosome formation, BECN1/Atg6 acts in association with PI3KIII/Vps34 as a platform that recruits activators and inhibitors of autophagy in order to finely regulate autophagosome formation (43). Two ubiquitin-like systems are fundamental for autophagosome enlargement and maturation downstream of BECN1. A first ubiquitin-like system is required for the formation of the Atg5-Atg12 complex, which contributes to autophagosomal membrane elongation (30, 39). The second ubiquitin-like system conjugates LC3 protein to phosphoethanolamine, allowing its incorporation into the autophagosomal membrane and subsequent autophagosome formation (56).In mammalian cells, metabolic stress and genotoxic stimuli, including ceramide and tamoxifen treatment, have been shown to trigger both apoptotic cell death and autophagy (51). A number of emerging pieces of evidence point to a prosurvival role for autophagy. Inactivation of the essential autophagy gene BECN1 results in apoptotic cell death in different mode...

show abstract

mentioning

confidence: 99%

p65/RelA Modulates BECN1 Transcription and Autophagy

Copetti

Bertoli

Dalla

et al. 2009

Molecular and Cellular Biology

239

179

View full text Add to dashboard Cite

show abstract

“…ATM inhibition downregulates NF-kB and induces apoptosis in the MDS/AML cell line P39 The presence of activated, phosphorylated ATM (on serine 1981) was monitored in four different AML cell lines, KG1 (which normally does not harbor constitutive NF-kB activity), MOLM-13, MV4-11 and P39 (which all exhibit constitutive NF-kB activation; Braun et al, 2006a;Fabre et al, 2007). Only P39 cells exhibited a strong constitutive ATM phosphorylation, which could be inhibited by ATMI or KU55933 (Figures 2a and b).…”

Section: Resultsmentioning

confidence: 99%

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

et al. 2008

Self Cite

View full text Add to dashboard Cite

The anti-apoptotic transcription factor nuclear factor-jB (NF-jB) is constitutively activated in CD34 þ myeloblasts from high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Inhibition of NF-jB by suppressing the canonical NF-jB activation pathway, for instance by knockdown of the three subunits of the inhibitor of NF-jB (IjB) kinase (IKK) complex (IKK1, IKK2 and NEMO) triggers apoptosis in such cells. Here, we show that an MDS/AML model cell line exhibits a constitutive interaction, within the nucleus, of activated, S1981-phosphorylated ataxia telangiectasia mutated (ATM) with NEMO. Inhibition of ATM with two distinct pharmacological inhibitors suppressed the activating autophosphorylation of ATM, blocked the interaction of ATM and NEMO, delocalized NEMO as well as another putative NF-jB activator, PIDD, from the nucleus, abolished the activating phosphorylation of the catalytic proteins of the IKK complex (IKK1/2 on serines 176/180), enhanced the expression of IjBa and caused the relocalization of NF-jB from the nucleus to the cytoplasm, followed by apoptosis. Knockdown of ATM with small-interfering RNAs had a similar effect that could not be enhanced by knockdown of NEMO, PIDD and the p65 NF-jB subunit, suggesting that an ATM inhibition/ depletion truly induced apoptosis through inhibition of the NF-jB system. Pharmacological inhibition of ATM also induced the nucleocytoplasmic relocalization of p65 in malignant myeloblasts purified from patients with highrisk MDS or AML, correlating with the induction of apoptosis. Altogether, these results support the contention that constitutively active ATM accounts for the activation of NF-jB in high-risk MDS and AML.

show abstract

“…Autophagy stimulation has also been observed after the activation of NF-κB during the heat shock response [138]. However, in contrast to this stimulatory role of NF-κB in the regulation of autophagy, the inhibition of NF-κB favors TNFα-dependent and starvation-dependent autophagy [139,140]. Moreover, Schlottmann et al reported that activation of NF-κB prevents autophagy in macrophages by down-regulating the expression of Atg5 and Beclin 1 [141].…”

Section: Nf-κbmentioning

confidence: 99%

Overview of macroautophagy regulation in mammalian cells

et al. 2010

View full text Add to dashboard Cite

Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light of recent advances in our understanding of the formation of autophagosomes, which are double-membrane-bound vacuoles that sequester cytoplasmic cargos and deliver them to lysosomes. In most cases, this final step is preceded by a maturation step during which autophagosomes interact with the endocytic pathway. The discovery of AuTophaGyrelated genes has greatly increased our knowledge about the mechanism responsible for autophagosome formation, and there has also been progress in the understanding of molecular aspects of autophagosome maturation. Finally, the regulation of autophagy is now better understood because of the discovery that the activity of Atg complexes is targeted by protein kinases, and owing to the importance of nuclear regulation via transcription factors in regulating the expression of autophagy genes.

show abstract

NF-κB inhibition sensitizes to starvation-induced cell death in high-risk myelodysplastic syndrome and acute myeloid leukemia

Cited by 88 publications

References 35 publications

p65/RelA Modulates BECN1 Transcription and Autophagy

p65/RelA Modulates BECN1 Transcription and Autophagy

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

Overview of macroautophagy regulation in mammalian cells

Contact Info

Product

Resources

About