Transcription Factor RBPJ as a Molecular Switch in Regulating the Notch Response

Giaimo, Benedetto Daniele; Gagliani, Ellen K.; Kovall, Rhett A.; Borggrefe, Tilman

doi:10.1007/978-3-030-55031-8_2

Cited by 41 publications

(39 citation statements)

References 168 publications

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“…The capacity of NOTCH1 to induce MYC expression was also confirmed by later studies in CLL [ 57 , 145 , 146 ], mantle cell lymphoma (MCL) [ 147 ] and other non-hematological cancers [ 148 , 149 , 150 , 151 ]. In particular, the work of Ryan et al [ 147 , 152 ] revealed that the NOTCH1-responsive element active in MCL (and possibly also in CLL) is different from the one identified in T-ALL, located about 500 kb upstream of the MYC locus, and its usage is restricted to B cells.…”

Section: Functional Consequences Of Notch1 Mutation In Cllmentioning

confidence: 67%

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

Pozzo

Bittolo

Tissino

et al. 2022

Cancers

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The Notch signaling pathway plays a fundamental role for the terminal differentiation of multiple cell types, including B and T lymphocytes. The Notch receptors are transmembrane proteins that, upon ligand engagement, undergo multiple processing steps that ultimately release their intracytoplasmic portion. The activated protein ultimately operates as a nuclear transcriptional co-factor, whose stability is finely regulated. The Notch pathway has gained growing attention in chronic lymphocytic leukemia (CLL) because of the high rate of somatic mutations of the NOTCH1 gene. In CLL, NOTCH1 mutations represent a validated prognostic marker and a potential predictive marker for anti-CD20-based therapies, as pathological alterations of the Notch pathway can provide significant growth and survival advantage to neoplastic clone. However, beside NOTCH1 mutation, other events have been demonstrated to perturb the Notch pathway, namely somatic mutations of upstream, or even apparently unrelated, proteins such as FBXW7, MED12, SPEN, SF3B1, as well as physiological signals from other pathways such as the B-cell receptor. Here we review these mechanisms of activation of the NOTCH1 pathway in the context of CLL; the resulting picture highlights how multiple different mechanisms, that might occur under specific genomic, phenotypic and microenvironmental contexts, ultimately result in the same search for proliferative and survival advantages (through activation of MYC), as well as immune escape and therapy evasion (from anti-CD20 biological therapies). Understanding the preferential strategies through which CLL cells hijack NOTCH1 signaling may present important clues for designing targeted treatment strategies for the management of CLL.

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Section: Functional Consequences Of Notch1 Mutation In Cllmentioning

confidence: 67%

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

Pozzo

Bittolo

Tissino

et al. 2022

Cancers

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“…TST is mainly localized to mitochondria and catalyzes the conversion of thiosulfate and cyanide to thiocyanate and sulfite [ 55 ]. As molecular switches in regulating the notch response, transcription factor RBPJ involves in the regulation of the progression of a variety of tumors, such as colorectal cancer [ 56 ], lung cancer [ 57 ], hepatocellular carcinoma [ 58 ], glioblastoma [ 59 , 60 ], and prostate cancer [ 61 ]. As a member of the G protein family, GNA11 plays an important role in tumor progression [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Genomic Analysis of Abnormal DNAM Methylation in Parathyroid Tumors

Sun

et al. 2022

International Journal of Endocrinology

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Background. Parathyroid tumors are common endocrine neoplasias associated with primary hyperparathyroidism. Although numerous studies have studied the subject, the predictive value of gene biomarkers nevertheless remains low. Methods. In this study, we performed genomic analysis of abnormal DNA methylation in parathyroid tumors. After data preprocessing, differentially methylated genes were extracted from patients with parathyroid tumors by using t-tests. Results. After refinement of the basic differential methylation, 28241 unique CpGs (634 genes) were identified to be methylated. The methylated genes were primarily involved in 7 GO terms, and the top 3 terms were associated with cyst morphogenesis, ion transport, and GTPase signal. Following pathway enrichment analyses, a total of 10 significant pathways were enriched; notably, the top 3 pathways were cholinergic synapses, glutamatergic synapses, and oxytocin signaling pathways. Based on PPIN and ego-net analysis, 67 ego genes were found which could completely separate the diseased group from the normal group. The 10 most prominent genes included POLA1, FAM155 B, AMMECR1, THOC2, CCND1, CLDN11, IDS, TST, RBPJ, and GNA11. SVM analysis confirmed that this grouping approach was precise. Conclusions. This research provides useful data to further explore novel genes and pathways as therapeutic targets for parathyroid tumors.

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“…One possibility for the molecular basis of LBS synergy in C. elegans is that neighboring LBSs enhance LAG-1/CSL occupancy at the cluster. Like many transcription factors, CSL proteins rapidly bind and release sites with dwell times on the order of one or a few seconds (Falo-Sanjuan et al, 2019;Giaimo et al, 2021;Gomez-Lamarca et al, 2018) and yet their transcriptional bursts last for much longer (10 -70 minutes for sygl-1) (Falo-Sanjuan et al, 2019;Lammers et al, 2020;Lee et al, 2019). One can imagine that as LAG-1 releases from an LBS, the existence of a neighboring LBS increases its rebinding.…”

Section: Lbs Additivity and Synergymentioning

confidence: 99%

Notch-dependent DNA cis-regulatory elements and their dose-dependent control of C. elegans stem cell self-renewal

Lynch

Xue

Czerniak

et al. 2021

Preprint

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A long-standing biological question is how DNA cis-regulatory elements shape transcriptional patterns during metazoan development. The use of reporter constructs, cell culture and computational modeling has made enormous contributions to understanding this fundamental question, but analysis of regulatory elements in their natural developmental context is an essential but rarely used complement. Here, we edited Notch-dependent cis-regulatory elements in the endogenous C. elegans sygl-1 gene, which encodes a key stem cell regulator. We then analyzed the in vivo consequences of those mutations – on both gene expression (nascent transcripts, mRNA, protein) and stem cell maintenance. Mutation of a single element in a three-element homotypic cluster reduced expression as well as stem cell pool size by about half, while mutation of two elements essentially abolished them. We find that LBS number and LBS neighborhood are both important to activity: elements on separate chromosomes function additively, while elements in the same cluster act synergistically. Our approach of precise CRISPR/Cas9 gene editing coupled with quantitation of both molecular and biological readouts establishes a powerful model for in vivo functional analyses of DNA cis-regulatory elements.Summary statementNotch-dependent DNA cis-regulatory elements work together in their developmental context to shape a transcriptional gradient, control stem cell pool size, and govern differentiation onset.

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Transcription Factor RBPJ as a Molecular Switch in Regulating the Notch Response

Cited by 41 publications

References 168 publications

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

Genomic Analysis of Abnormal DNAM Methylation in Parathyroid Tumors

Notch-dependent DNA cis-regulatory elements and their dose-dependent control of C. elegans stem cell self-renewal

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