TAp73 is required for macrophage-mediated innate immunity and the resolution of inflammatory responses

Tomasini, Richard; Secq, Véronique; Pouyet, Laurent; Thakur, A K; Wilhelm, Margareta; Nigri, Jérémy; Vasseur, Sophie; Berthézène, P.; Calvo, Ézéquiel; Melino, G; Mak, Tak W.; Iovanna, Juan

doi:10.1038/cdd.2012.123

Cited by 29 publications

(30 citation statements)

References 40 publications

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“…Moreover, the increased level of free TGF-β can also favor immune suppression 56 with an accumulation of tumor-associated macrophages, on which TAp73 deletion has been shown to impact. 24 Future studies could therefore consider investigating the potential role of TAp73 in PDA-associated immune response. Altogether, our data suggest that both in-cell modifications and paracrine effects brought about by TAp73 deficiency force a switch in function of TGF-β in carcinogenesis from tumor suppressive to tumor promoting (Figure 7), and thereby refine our understanding and clinical translation of TGF-β modulation.…”

Section: Discussionmentioning

confidence: 99%

“…21 Moreover, although mutations in TP73 are less frequent in human cancers than those of TP53, genetic aberrations of TP73 were reported in pancreatic cancer and correlated with patient outcome. 22 Based on the known impact of p53 in human and mouse models of PDA, 23 and on the potential role of TAp73 in inflammation and cancer crosstalk, 24 we wished to deepen our knowledge of TAp73 roles and functions in PDA.…”

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confidence: 99%

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TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

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Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-β (TGF-β) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-β pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/ activity. Absence of TAp73 leads to activation of TGF-β signaling through a SMAD-independent pathway, favoring oncogenic TGF-β effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-β signaling. By suggesting TAp73 as a predictive marker for response to TGF-β inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-β inhibitors.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

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“…[16][17][18][19][20][21] Here, the cellular defense to DNA damage is based on sensors and effectors that activates the cell death pathway, [22][23][24] via p53 [25][26][27][28][29] or its family members. [30][31][32][33][34][35][36][37] Like for our recent Itch inhibitor screening, 14 we believe that in a near future innovative E3 inhibitors will be developed. Here, however, we adopted a different approach to inhibit their function, based on a deeper understanding of the interaction of Itch with its substrate.…”

Section: Introductionmentioning

confidence: 99%

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

et al. 2014

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Both in epithelial development as well as in epithelial cancers, the p53 family member p63 plays a crucial role acting as a master transcriptional regulator. P63 steady state protein levels are regulated by the E3 ubiquitin ligase Itch, via a physical interaction between the PPxY consensus sequence (PY motif) of p63 and one of the 4 WW domains of Itch; this substrate recognition process leads to protein-ubiquitylation and p63 proteasomal degradation. The interaction of the WW domains, a highly compact protein-protein binding module, with the short proline-rich sequences is therefore a crucial regulatory event that may offer innovative potential therapeutic opportunity. Previous molecular studies on the Itch-p63 recognition have been performed in vitro using the Itch-WW2 domain and the peptide interacting fragment of p63 (pep63), which includes the PY motif. Itch-WW2-pep63 interaction is also stabilized in vitro by the conformational constriction of the S-S cyclization in the p63 peptide. The PY motif of p63, as also for other proteins, is characterized by the nearby presence of a (T/S)P motif, which is a potential recognition site of the WW domain of the IV group present in the prolyl-isomerase Pin1. In this study, we demonstrate, by in silico and spectroscopical studies using both the linear pep63 and its cyclic form, that the threonine phosphorylation of the (T/S)PPPxY motif may represent a crucial regulatory event of the Itch-mediated p63 ubiquitylation, increasing the Itch-WW domains-p63 recognition event and stabilizing in vivo the Itch-WW-p63 complex. Moreover, our studies confirm that the subsequently trans/cis proline isomerization of (T/S)P motif by the Pin1 prolyl-isomerase, could modulate the E3-ligase interaction, and that the (T/S) p P trans PPxY motif represent the best conformer for the ItchWW-(T/S)PPPxY motif recognition.

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“…1,2 Polarized macrophages is often simplified into two broad opposing categories: classical activated macrophages, termed M1, induced by microbial ligands and cytokines such as lipopolysaccharide (LPS) and interferon-g (IFN-g) or granulocyte-macrophage colony-stimulating factor (GM-CSF), and alternative activated macrophages, termed M2, as a result of exposure to IL-4, IL-13, IL-10, glucocorticoids, and immune complexes plus TLR ligands. [3][4][5] While M1 macrophages produce pro-inflammatory mediators such as tumor necrosis factor-a (TNF-a), IL-6, IL-12, IL-23, and NO, and have a role in killing intracellular microorganisms, M2 macrophages produce anti-inflammatory mediators such as IL-4, IL-5, IL-10, and IL-13, and are important in atopic disease, parasite response, and tumor progression. [6][7][8] The diverse polarized phenotypes of M1-M2 macrophages can, to some extent, be dynamically reversed in vitro and in vivo.…”

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confidence: 99%

Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-κB pathway

Zhang

Liu

et al. 2014

Cell Death Differ

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Serine/threonine kinase family members p21-activated kinases (PAKs) are important regulators of cytoskeletal remodeling and cell motility in mononuclear phagocytic system, but their role in macrophage differentiation and polarization remains obscure. We have shown here that inflammatory stimuli induced PAK1 overexpression in human and murine macrophages. Elevated expression of PAK1 contributed to macrophage M1 polarization and lipopolysaccharide (LPS)-induced endotoxin shock. We further observed that epigenetic loss of microRNA let-7c due to enhancer of zeste homolog 2 (EZH2) upregulation determined PAK1 elevation and inflammatory phenotype in M1 macrophages. EZH2/let-7c/PAK1 axis promotes macrophage M1 polarization via NIK-IKK-NF-jB signaling. Moreover, pharmacological and genetic ablation with EZH2/let-7c/PAK1 axis blunted inflammatory phenotype in M1 macrophages. Critically, either myeloid-restricted PAK1 deletion (PAK1 Lyz2cre ) or pharmacological and genetic ablation with EZH2/let-7c/PAK1 signal resulted in resistance to LPS-induced endotoxin shock via blunting macrophage M1 polarization. PAK1, therefore, is an essential controller of inflammatory macrophage polarization, regulating immune responses against pathogenic stimuli.

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TAp73 is required for macrophage-mediated innate immunity and the resolution of inflammatory responses

Cited by 29 publications

References 40 publications

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-κB pathway

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