<i><scp>LITAF</scp></i>, a <scp>BCL</scp>6 target gene, regulates autophagy in mature B‐cell lymphomas

Bértolo, Cristina; Roa, Sergio; Sagardoy, Ainara; Mena-Varas, Maria; Robles, Eloy F.; Martinez-Ferrandis, Jose I.; Tousseyn, Thomas; Orta, Alberto; Amar, Salomon; Natkunam, Yasodha; Briones, Javier; Melnick, Ari; Malumbres, Raquel; Martínez-Climent, José A.

doi:10.1111/bjh.12440

Cited by 39 publications

(37 citation statements)

References 49 publications

(60 reference statements)

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“…A recent study for the first time has demonstrated that LITAF , a novel target of BCL6, regulates autophagy in mature B-cell lymphomas [14]. This study provided evidences for the transcriptional repression of LITAF by BCL6 in B cells.…”

Section: Resultssupporting

confidence: 53%

“…Recent studies have showed, both mRNA and protein expression of LITAF are significantly down-regulated in germinal centre (GC) B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL), which display constitutively high BCL6 expression [11–13]. Interestingly, it has been demonstrated that LITAF is a novel target of BCL6 [14], providing new insights into the crosstalk between BCL6 and LITAF. In fact, BCL6 is a transcriptional repressor of the POZ/BTB zinc-finger protein family, acting as a key regulator for development of the germinal center (GC) and further differentiation [15].…”

Section: Introductionmentioning

confidence: 99%

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The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma

et al. 2016

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Dysregulation of the apoptotic pathway is widely recognized as a key step in lymphomagenesis. Notably, LITAF was initially identified as a p53-inducible gene, subsequently implicated as a tumor suppressor. Our previous study also showed LITAF to be methylated in 89.5% B-NHL samples. Conversely, deregulated expression of BCL6 is a pathogenic event in many lymphomas. Interestingly, our study found an oppositional expression of LITAF and BCL6 in B-NHL. In addition, LITAF was recently identified as a novel target gene of BCL6. Therefore, we sought to explore the feedback loop between LITAF and BCL6 in B-NHL. Here, our data for the first time show that LITAF can repress expression of BCL6 by binding to Region A (−87 to +65) containing a putative LITAF-binding motif (CTCCC) within the BCL6 promoter. Furthermore, the regulation of BCL6 targets (PRDM1 or c-Myc) by LITAF may be associated with B-cell differentiation. Results also demonstrate that ectopic expression of LITAF induces cell apoptosis, activated by releasing cytochrome c, cleaving PARP and caspase 3 in B-NHL cells whereas knockdown of LITAF robustly protected cells from apoptosis. Interestingly, BCL6, in turn, could reverse cell apoptosis mediated by LITAF. Collectively, our findings provide a novel apoptotic regulatory pathway in which LITAF, as a transcription factor, inhibits the expression of BCL6, which leads to activation of the intrinsic mitochondrial pathway and tumor apoptosis. Our study is expected to provide a possible biomarker as well as a target for clinical therapies to promote tumor cell apoptosis.

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Section: Resultssupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma

et al. 2016

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“…In addition, BCL6 is involved in the development of CD4+ T-follicular helper cells that play a critical role during the generation of germinal centers (Yu et al, 2009; Hollister et al, 2013). Thus, most B cell lymphomas arise from GC B cells need continued expression of BCL6 to maintain their survival (Hatzi et al, 2013; Bertolo et al, 2013). Targeted inhibition of these BCL6 functions has emerged as the basis for the rational design of lymphoma therapies and combinatorial regimens.…”

Section: Introductionmentioning

confidence: 99%

miR-10a inhibits cell proliferation and promotes cell apoptosis by targeting BCL6 in diffuse large B-cell lymphoma

et al. 2016

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The BCL6 (B-Cell Lymphoma 6) gene is a proto-oncogene that is often expressed in diffuse large B-cell lymphomas (DLBCLs). BCL6 loss of function can kill DLBCL cells, demonstrating that BCL6 is necessary for the survival of DLBCL cells and could be a therapeutic target. In this study, we found that BCL6 protein levels were consistently upregulated in DLBCL tissues, whereas its mRNA levels varied randomly in tissues, suggesting that a post-transcriptional mechanism was involved in BCL6 regulation. We used bioinformatics analysis to search for miRNAs, which potentially target BCL6, and identified specific targeting sites for miR-10a in the 3′-untranslated region (3′-UTR) of BCL6. We further identified an inverse correlation between miR-10a levels and BCL6 protein levels, but not mRNA levels, in DLBCL tumor tissue samples. By overexpressing or knocking down miR-10a in DLBCL cells, we experimentally validated that miR-10a directly recognizes the 3′-UTR of the BCL6 transcript and regulated BCL6 expression. Furthermore, we demonstrated that negatively regulating BCL6 by miR-10a suppressed the proliferation and promoted apoptosis of DLBCL cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-016-0316-z) contains supplementary material, which is available to authorized users.

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“…In addition to peripheral neuropathy, dysregulation of SIMPLE is also associated with arrhythmias and sudden cardiac death in patients with idiopathic prolonged QT interval duration (LQT syndrome) (70,71). SIMPLE also contributes to tumorigenesis (72)(73)(74), in which inflammatory pathways such as those utilized by IL-1 and TGF-␤ are frequently altered.…”

Section: T115n/t115nmentioning

confidence: 99%

Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type 1C Mutation of SIMPLE Protein

Zhu

Zhao

et al. 2015

Molecular and Cellular Biology

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Endosomal trafficking is a key mechanism to modulate signal propagation and cross talk. Ubiquitin adaptors, along with endosomal sorting complex required for transport (ESCRT) complexes, are also integrated to terminate ligand-receptor activation in late endosomes and multivesicular bodies (MVBs). Within these pathways, we recently demonstrated that the protein SIMPLE is a novel player in MVB regulation. SIMPLE is also clinically important and its mutation accounts for the Charcot-Marie-Tooth type 1C (CMT1C) disease. MVB defects of mutation and deletion of SIMPLE, however, are distinct. Here, we show that MVB defects found in mutation but not deletion of SIMPLE lead to impaired turnover and accumulation of ESCRT-0 protein Hrs puncta in late endosomes. We further uncover increased colocalization of ubiquitin ligase TRAF6 and Hrs in late endosomes. Upon stimulation with interkeukin-1 or transforming growth factor ␤, prolonged activation of p38 kinase/JNK is detected, while nuclear accumulation of NF-B and phosphorylation of SMAD2 is reduced with CMT1C mutation. The aberrant kinetics we observed in inflammatory signaling may contribute to increased tumor susceptibility and changes in the levels of chemokines/cytokines that result from CMT1C mutation. We propose that altered endosomal trafficking due to malformations of MVBs and subsequent atypical signaling kinetic may account for a toxic gain of function in CMT1C pathogenesis.

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LITAF, a BCL6 target gene, regulates autophagy in mature B‐cell lymphomas

Cited by 39 publications

References 49 publications

The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma

The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma

miR-10a inhibits cell proliferation and promotes cell apoptosis by targeting BCL6 in diffuse large B-cell lymphoma

Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type 1C Mutation of SIMPLE Protein

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