The miR-17∼92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes

Bomben, Riccardo; Gobessi, Stefania; Bo, Michele Dal; Volinia, Stefano; Marconi, Daniela; Tissino, Erika; Benedetti, Dania; Zucchetto, Antonella; Rossi, Davide; Gaïdano, Gianluca; Poeta, Giovanni Del; Laurenti, Luca; Efremov, Dimitar G.; Gattei, Valter

doi:10.1038/leu.2012.44

Cited by 77 publications

(74 citation statements)

References 61 publications

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“…Bottom panel shows a densitometric quantification of bands from the Ni 2 þ pull down assay TP53INP1 SUMOylation modulates p53 activity S Peuget et al micro-RNA, including miR-17, miR-93, miR-125b, miR-130b and miR-155. 15,[38][39][40] In this work, we add a third layer on the complex TP53INP1 regulation, through its redox-dependent post-translational modifications. This reinforces the hypothesis that p53 regulators such as TP53INP1 are very important in cell fate decision, and shed light to their tumor suppressor mechanism of action.…”

Section: Resultsmentioning

confidence: 99%

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation

et al. 2014

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Tumor Protein p53-Induced Nuclear Protein 1 (TP53INP1) is a tumor suppressor that modulates the p53 response to stress. TP53INP1 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes. TP53INP1 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development. In this work, we report that redox-dependent induction of p53 transcriptional activity is enhanced by the oxidative stress-induced SUMOylation of TP53INP1 at lysine 113. This SUMOylation is mediated by PIAS3 and CBX4, two SUMO ligases especially related to the p53 activation upon DNA damage. Importantly, this modification is reversed by three SUMO1-specific proteases SENP1, 2 and 6. Moreover, TP53INP1 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions. TP53INP1 mutation at lysine 113 prevents the pro-apoptotic, antiproliferative and antioxidant effects of TP53INP1 by impairing the p53 response on its target genes p21, Bax and PUMA. We conclude that TP53INP1 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress. Cell Death and Differentiation (2014) 21, 1107-1118; doi:10.1038/cdd.2014.28; published online 7 March 2014Maintaining homeostasis in response to the broad range of intrinsic and extrinsic aggressions is a challenge for cells. Cellular outcomes are varied and involve cell-cycle arrest, apoptosis, DNA repair, autophagy, senescence, antioxidant activity, cell migration, differentiation, embryo implantation, metabolism and angiogenesis.1-9 An inadequate cell response can lead to cellular transformation and cancer initialization. Tumor Protein p53-Induced Nuclear Protein 1 (TP53INP1) is a p53 cofactor. The gene TP53INP1 encodes for two protein isoforms generated by alternative splicing, named TP53INP1a and TP53INP1b. TP53INP1 is a p53 target gene and its expression is induced in response to several physical and chemical stresses.10-12 TP53INP1 directly interacts with p53 and also binds kinases, such as HIPK2 and PKCd, which modulate p53 transcriptional activity by phosphorylation, thereby creating a positive feedback loop between p53 and TP53INP1.13,14 Our laboratory demonstrated the role of TP53INP1 as a tumor suppressor as TP53INP1-deficient mice present an increased susceptibility to tumor development. Moreover, TP53INP1 expression is lost at very early steps of pancreatic carcinogenesis due to miR155 activity and, when its expression is restored in pancreatic cancer cells, it suppresses growth of xenograft tumors by favoring apoptotic cell death. 15,16 Interestingly, the role of TP53INP1 as a tumor suppressor is associated with its ability to enhance the p53 antioxidant function. 17 In accordance, TP53INP1 transcriptional induction upon oxidative stress is strictly dependent on p53, and TP53INP1-deficient cells accumulate more intracellular reactive oxygen species (ROS) than wild-type cells. This ROS accumulation is...

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Section: Resultsmentioning

confidence: 99%

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation

et al. 2014

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“…4,26 However, no obvious correlation was seen between the ability of IL-6 to tolerize TLR7 responses and clinical patient characteristics (supplemental Table 1). CLL cells with 17 deletions and loss of p53 function exhibit especially aberrant responses to cytokines and TLR ligands.…”

Section: Inhibition Of Tlr7 Signaling By Splenic Stromal Factorsmentioning

confidence: 94%

Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A

Shi

McCaw

et al. 2015

Blood

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Key Points• IL-6 from splenic stromal cells prevents CLL cells from responding strongly to TLR ligands.• IL-6-signaling inhibitors enhance TLR-mediated responses of CLL cells in vitro and in vivo.The regulation of toll-like receptor (TLR) signaling in a tumor microenvironment is poorly understood despite its importance in cancer biology. To address this problem, TLR7-responses of chronic lymphocytic leukemia (CLL) cells were studied in the presence and absence of a human stromal cell-line derived from a leukemic spleen. CLL cells alone produced high levels of tumor necrosis factor (TNF)-a and proliferated in response to TLR7-agonists. A signal transducer and activator of transcription 3 -activating stromal factor, identified as interleukin (IL)-6, was found to upregulate microRNA (miR)-17 and miR-19a, target TLR7 and TNFA messenger RNA, and induce a state of tolerance to TLR7-agonists in CLL cells. Overexpression of the miR-17-92 cluster tolerized CLL cells directly and miR-17 and miR-19a antagomiRs restored TLR7-signaling. Inhibition of IL-6 signaling with antibodies or small-molecule Janus kinase inhibitors reversed tolerization and increased TLR7-stimulated CLL cell numbers in vitro and in NOD-SCIDg c null mice. These results suggest IL-6 can act as tumor suppressor in CLL by inhibiting TLR-signaling. (Blood. 2015;126(6):766-778)

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“…Recent evidence suggests that miRNAs target key molecules of the B-cell immune pathways (20,44,45). With this in mind and also taking into account that several miRNAs are differentially expressed in CLL, we investigated whether miRNAs could also be implicated in the D 1 9 : 1 1 5 -1 2 3 , 2 distinct immune signaling profiles of CLL subgroups with different clinical presentation and outcome.…”

Section: Discussionmentioning

confidence: 99%

“…These findings may be relevant for the observed inconsistencies between miRNA, mRNA and protein expression of MAPK8 and FOS in the studied CLL cases, indicating the need for further investigation. All that notwithstanding, it is worth mentioning that our analyses were conducted at basal level without any form of stimulation, which is relevant in view of recent reports by us (52) and others (44) that the triggering of immune receptors modulates miRNA expression in CLL, alluding to autoregulatory control.…”

Section: R E S E a R C H A R T I C L E M O L M Ementioning

confidence: 99%

Differential microRNA Profiles and Their Functional Implications in Different Immunogenetic Subsets of Chronic Lymphocytic Leukemia

Papakonstantinou

Ntoufa

Chartomatsidou

et al. 2013

Mol Med

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Critical processes of B-cell physiology, including immune signaling through the B-cell receptor (BcR) and/or Toll-like receptors (TLRs), are targeted by microRNAs. With this in mind and also given the important role of BcR and TLR signaling and microRNAs in chronic lymphocytic leukemia (CLL), we investigated whether microRNAs could be implicated in shaping the behavior of CLL clones with distinct BcR and TLR molecular and functional profiles. To this end, we examined 79 CLL cases for the expression of 33 microRNAs, selected on the following criteria: (a) deregulated in CLL versus normal B-cells; (b) differentially expressed in CLL subgroups with distinct clinicobiological features; and, (c) if meeting (a) + (b), having predicted targets in the immune signaling pathways. Significant upregulation of miR-150, miR-29c, miR-143 and miR-223 and downregulation of miR-15a was found in mutated versus unmutated CLL, with miR-15a showing the highest fold difference. Comparison of two major subsets with distinct stereotyped BcRs and signaling signatures, namely subset 1 [IGHV1/5/7-IGKV1(D)-39, unmutated, bad prognosis] versus subset 4 [IGHV4-34/IGKV2-30, mutated, good prognosis] revealed differences in the expression of miR-150, miR-29b, miR-29c and miR-101, all down-regulated in subset 1. We were also able to link these distinct microRNA profiles with cellular phenotypes, importantly showing that, in subset 1, miR-101 downregulation is associated with overexpression of the enhancer of zeste homolog 2 (EZH2) protein, which has been associated with clinical aggressiveness in other B-cell lymphomas. In conclusion, specific miRNAs differentially expressed among CLL subgroups with distinct BcR and/or TLR signaling may modulate the biological and clinical behavior of the CLL clones.

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The miR-17∼92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes

Cited by 77 publications

References 61 publications

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation

Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A

Differential microRNA Profiles and Their Functional Implications in Different Immunogenetic Subsets of Chronic Lymphocytic Leukemia

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