Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics

Lalaoui, Najoua; Hänggi, Kay; Brumatti, Gabriela; Chau, Diep; Nguyen, Nhu-Y; Vasilikos, Lazaros; Spilgies, Lisanne M.; Heckmann, Denise A.; Ma, Chunyan; Ghisi, Margherita; Salmon, Jessica M.; Matthews, Geoffrey M.; Valle, Elisha de; Moujalled, Donia; Menon, Manoj B.; Spall, Sukhdeep K; Glaser, Stefan; Richmond, Jennifer; Lock, Richard B.; Condon, Stephen M.; Gugasyan, Raffi; Gaestel, Matthias; Guthridge, Mark A.; Johnstone, Ricky W.; Munoz, Lenka; Wei, Andrew H.; Ekert, Paul G.; Vaux, David L.; Wong, Wendy Wei-Lynn; Silke, John

doi:10.1016/j.ccell.2016.01.006

Cited by 92 publications

(65 citation statements)

References 54 publications

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“…p38 and ERK signaling are implicated in AML cell proliferation (Birkenkamp et al, 1999). p38 inhibition enhances the anti-leukemic activity of Birinapant, a smac mimetic (Lalaoui et al, 2016). Besides MAPK inhibitors, HSP90 inhibitors suppress ERK signaling (Zong et al, 2015) and Rac inhibitors suppress p38 signaling (Zhang et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells

et al. 2016

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SUMMARY The master regulatory transcription factor GATA-2 triggers hematopoietic stem and progenitor cell generation. GATA2 haploinsufficiency is implicated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and GATA2 overexpression portends a poor prognosis for AML. However, the constituents of the GATA-2-dependent genetic network mediating pathogenesis are unknown. We described a p38-dependent mechanism that phosphorylates GATA-2 and increases GATA-2 target gene activation. We demonstrate that this mechanism establishes a growth-promoting chemokine/cytokine circuit in AML cells. p38/ERK-dependent GATA-2 phosphorylation facilitated positive autoregulation of GATA2 transcription and expression of target genes, including IL1B and CXCL2. IL-1β and CXCL2 enhanced GATA-2 phosphorylation, which increased GATA-2-mediated transcriptional activation. p38/ERK-GATA-2 stimulated AML cell proliferation via CXCL2 induction. As GATA2 mRNA correlated with IL1B and CXCL2 mRNAs in AML-M5 and high expression of these genes predicted poor prognosis of cyto-genetically normal AML, we propose that the circuit is functionally important in specific AML contexts.

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Section: Discussionmentioning

confidence: 99%

GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells

et al. 2016

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“…During TLR signaling, activation of the p38MAPK-MK2 pathway promotes the stabilization of TNF expression (58). In contrast, during ripoptosome signaling in myeloid leukemia cells, p38MAPK has been shown to inhibit TNF expression, and inhibition of MK2 results in enhanced cell death of leukemia cells (59). It was subsequently shown that MK2 mediates an inhibitory phosphorylation of RipK1, which restricts ripoptosome induced cell death (60)(61)(62).…”

Section: Discussionmentioning

confidence: 99%

Differentiated macrophages acquire a pro-inflammatory and cell death–resistant phenotype due to increasing XIAP and p38-mediated inhibition of RipK1

Rijal

Ariana

Wight

et al. 2018

Journal of Biological Chemistry

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Monocytes differentiate into macrophages, which deactivate invading pathogens. Macrophages can be resistant to cell death mechanisms in some situations and the mechanisms involved are not clear. Here, using mouse immune cells, we investigated whether the differentiation of macrophages affects their susceptibility to cell death by the ripoptosome/necrosome pathways. We show that treatment of macrophages with a mimetic of second mitochondrial activator of caspases (SMAC) resulted in ripoptosome driven cell death that specifically depended on tumor necrosis factor  (TNF expression and the receptor-interacting serine/threonine protein kinase 1 (RipK1)-RipK3-caspase-8 interaction in activated and cycling macrophages. Differentiation of macrophages increased the expression of proinflammatory cytokines but reduced RipK1-dependent cell death and the RipK3-caspase-8 interaction. The expression of the antiapoptotic mediators, X-linked inhibitor of apoptosis protein (XIAP) and caspase-like apoptosis regulatory protein (cFLIPL) also increased in differentiated macrophages, which inhibited caspase activation. The resistance to cell death was abrogated in XIAP-deficient macrophages. However, even in the presence of increased XIAP expression, inhibition of the mitogenactivated protein kinase (MAPK) p38 and MAPK-activated protein kinase 2 (MK2) made differentiated macrophages susceptible to cell death. These results suggest that the p38/MK2 pathway overrides apoptosis inhibition by XIAP, and that acquisition of resistance to cell death by increased expression of XIAP and cFLIPL may allow inflammatory macrophages to participate in pathogen control for a longer duration. ____________________________________ http://www.jbc.org/cgi

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“…Consequently, several pharmaceutical compounds have been developed to target these kinases in auto-inflammatory diseases (Genovese, 2009). However, recently we proposed that the p38-MK2 axis also regulates TNF- and RIPK1-dependent SMAC-mimetic (SM)-induced cell death (Lalaoui et al., 2016). These results therefore suggest that TAK1 mediates its pro-survival effect, at least in part, through activation of p38-MK2 (Sakurai, 2012).…”

Section: Introductionmentioning

confidence: 99%

MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death

et al. 2017

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SummaryTNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.

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Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics

Cited by 92 publications

References 54 publications

GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells

GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells

Differentiated macrophages acquire a pro-inflammatory and cell death–resistant phenotype due to increasing XIAP and p38-mediated inhibition of RipK1

MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death

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