scholarly journals CSIG-20. L3MBTL3 SUPPRESSES MEDULLOBLASTOMA TUMORIGENESIS THROUGH MODULATION OF THE NOTCH/RBPJ SIGNALING PATHWAY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii32-ii32
Author(s):  
Honglai Zhang ◽  
Tao Xu ◽  
Claire Peabody ◽  
Ester Calvo Fernández ◽  
Rashmi Budhathoki ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Tumor Suppressor ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Cell Fate ◽  
Target Genes ◽  
Genetically Engineered ◽  
Rank Test ◽  
Rna Seq

Abstract The NOTCH/RBPJ pathway governs cell proliferation in many biological contexts, including SHH and Group#3medulloblastoma (MB) tumorigenesis. Using our proteomic platform, we discovered an interaction between RBPJ, a key co-factor of NOTCH for the modulation of the NOTCH/RBPJ signaling pathway, and L3MBTL3, a methyllysine reader. L3MBTL3 is recruited by RBPJ on chromatin at the enhancers of NOTCH/RBPJ target genes to repress their expression. Deletions of the L3MBTL3 locus are observed in patients with WNT and Group#3 MB and expression of L3MBTL3 in the SHH MB-derived cell DAOY inhibits cell growth, suggesting a putative tumor suppressor role for L3MBTL3 in MB. To further investigate the putative role of L3MBTL3 as a suppressor of MB tumorigenesis, we used our novel L3mbtl3 KO mouse in combination with a genetically engineered ND2:SmoA1 mouse model of SHH MB in a survival analysis. Furthermore, to identify the biological processes regulated by L3mbtl3 in MB, we analyzed by RNA-seq the transcriptome of L3mbtl3 KO mouse cerebella. Our survival analysis validated in vivo our hypothesis that L3mbtl3 is a tumor suppressor in this disease context. Indeed, our data show that [ND2:SmoA1; L3mbtl3+/-] mice have a significantly lower survival rate than ND2:SmoA1 mice (P = 0.032; Log-rank test). Moreover, our RNA-seq studies showed that L3MBTL3 regulates cell fate in the cerebellum via modulation the NOTCH/RBPJ signaling pathway. Hence, the RBPJ-L3MBTL3 interaction is at the heart of a molecular mechanism governing the repression of NOTCH/RBPJ target genes and malfunction of this molecular mechanism contributes to L3MBTL3’s tumor suppressor role in MB through aberrant “de-repression” of NOTCH/RBPJ target genes. Our discovery provides insights into the tumor suppressor role of the L3MBTL3 in MB that could be harnessed in the future for the therapeutic benefit of patients with MB.

scholarly journals OS12.3 L3MBTL3 is a novel suppressor of medulloblastoma tumorigenesis

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii22-iii23
Author(s):  
J Rual
Keyword(s):  
Survival Analysis ◽  
Tumor Suppressor ◽  
Molecular Mechanism ◽  
Target Genes ◽  
Therapeutic Benefit ◽  
Genetically Engineered ◽  
Rank Test ◽  
Therapeutic Approaches ◽  
Lower Survival Rate

Abstract BACKGROUND Medulloblastoma is the most common malignant brain tumor of childhood. Therapeutic approaches to medulloblastoma have led to significant improvements but are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed and molecular stratification of patients with medulloblastoma has yet to be routinely implemented in the clinic. TheNotchpathway governs cell proliferation in many biological contexts, including SHHand Group#3medulloblastoma tumorigenesis. Using our proteomic platform, we discovered an interaction between RBPJ, a key co-factor of Notch for the modulation of Notch signals, and L3MBTL3, a methyllysine reader.L3MBTL3 is recruited by RBPJ on chromatin at the enhancers of Notch/RBPJ target genes to repress their expression.Deletions ofthe L3MBTL3locus are observed in patientswith WNTand Group#3medulloblastomaand expression of L3MBTL3 in the SHHmedulloblastoma-derived cell DAOY inhibits cell growth, suggesting a putative tumor suppressor role for L3MBTL3 in medulloblastoma. METHODS To further investigate the putative role of L3MBTL3 as a suppressor of medulloblastoma tumorigenesis, we used our novel L3mbtl3KO mouse in combination with a genetically engineered ND2:SmoA1mouse model of SHHmedulloblastoma in a survival analysis. RESULTS Our survival analysis validated in vivoour hypothesis that L3mbtl3is a tumor suppressor in this disease context. Indeed, our data show that [ND2:SmoA1; L3mbtl3+/-] mice have a significantly lower survival rate than ND2:SmoA1 mice (P= 0.0322; Log-rank test). Hence, the RBPJ-L3MBTL3 interaction is at the heart of a molecular mechanism governing the repression of Notch/RBPJ target genes and malfunction of this molecular mechanism contributes to L3MBTL3’s tumor suppressor role in medulloblastomathrough aberrant “de-repression” of Notch/RBPJ target genes. CONCLUSION L3MBTL3 is a novel suppressor of medulloblastoma tumorigenesis. Our discovery providesinsights into the role of the L3MBTL3 inmedulloblastomathat could be harnessed in the future for the therapeutic benefit of patientswith medulloblastoma.

scholarly journals Targeting HSPA1A in ARID2-deficient lung adenocarcinoma

2021 ◽  
Author(s):  
Xue Wang ◽  
Yuetong Wang ◽  
Zhaoyuan Fang ◽  
Hua Wang ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Genetically Engineered ◽  
Malignant Progression ◽  
Murine Models ◽  
Rna Seq ◽  
Potential Therapeutic Target ◽  
Lung Cancers ◽  
Integrative Analyses

Abstract Somatic mutations of the chromatin remodeling gene ARID2 are observed in about 7% of human lung adenocarcinoma (LUAD). However, the role of ARID2 in the pathogenesis of LUAD remains largely unknown. Here we find that ARID2 expression is decreased during the malignant progression of both human and mice LUAD. Using two KrasG12D-based genetically engineered murine models (GEMM), we demonstrate that ARID2 knockout significantly promotes lung cancer malignant progression and shortens the overall survival. Consistently, ARID2 knockdown significantly promotes cell proliferation in human and mice lung cancer cells. Through integrative analyses of Chip-Seq and RNA-Seq data, we find that Hspa1a is up-regulated by Arid2 loss. Knockdown of Hspa1a specifically inhibits malignant progression of Arid2-deficient but not Arid2-wt lung cancers in both cell lines as well as animal models. Treatment with Hspa1a inhibitor could significantly inhibit the malignant progression of lung cancer with Arid2 deficiency. Together, our findings establish ARID2 as an important tumor suppressor in LUAD with novel mechanistic insights, and further identify HSPA1A as a potential therapeutic target in ARID2-deficient LUAD.

Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1154-1162 ◽  
Author(s):  
Wei Zheng ◽  
Tuomas Tammela ◽  
Masahiro Yamamoto ◽  
Andrey Anisimov ◽  
Tanja Holopainen ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Notch Pathway ◽  
Lymphatic Vessels ◽  
Soluble Form ◽  
Fibrin Gel ◽  
3 Dimensional ◽  
Endothelial Growth Factor

Abstract Notch signaling plays a central role in cell-fate determination, and its role in lateral inhibition in angiogenic sprouting is well established. However, the role of Notch signaling in lymphangiogenesis, the growth of lymphatic vessels, is poorly understood. Here we demonstrate Notch pathway activity in lymphatic endothelial cells (LECs), as well as induction of delta-like ligand 4 (Dll4) and Notch target genes on stimulation with VEGF or VEGF-C. Suppression of Notch signaling by a soluble form of Dll4 (Dll4-Fc) synergized with VEGF in inducing LEC sprouting in 3-dimensional (3D) fibrin gel assays. Expression of Dll4-Fc in adult mouse ears promoted lymphangiogenesis, which was augmented by coexpressing VEGF. Lymphangiogenesis triggered by Notch inhibition was suppressed by a monoclonal VEGFR-2 Ab as well as soluble VEGF and VEGF-C/VEGF-D ligand traps. LECs transduced with Dll4 preferentially adopted the tip cell position over nontransduced cells in 3D sprouting assays, suggesting an analogous role for Dll4/Notch in lymphatic and blood vessel sprouting. These results indicate that the Notch pathway controls lymphatic endothelial quiescence, and explain why LECs are poorly responsive to VEGF compared with VEGF-C. Understanding the role of the Notch pathway in lymphangiogenesis provides further insight for the therapeutic manipulation of the lymphatic vessels.

scholarly journals Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

2015 ◽  
Vol 112 (5) ◽  
pp. E402-E409 ◽  
Author(s):  
Marcelo Boareto ◽  
Mohit Kumar Jolly ◽  
Mingyang Lu ◽  
José N. Onuchic ◽  
Cecilia Clementi ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Tumor Stroma ◽  
Notch Receptor ◽  
Toggle Switch ◽  
Cell Fate Determination ◽  
Asymmetric Effect ◽  
Fate Determination

Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.

scholarly journals The role of miRNA-377 as a tumor suppressor in lung cancer by negative regulation of genes belonging to ErbB signaling pathway

2021 ◽  
Author(s):  
Saba Hashemi ◽  
Naghmeh Yari ◽  
Fatemeh Rahimi Jamnani ◽  
Reza Mahdian ◽  
Morteza Karimi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Signaling Pathway ◽  
Negative Regulation ◽  
Erbb Signaling ◽  
Erbb Signaling Pathway

scholarly journals Study on the role of JAK/STAT signaling pathway during chicken spermatogonial stem cells generation based on RNA-Seq

2015 ◽  
Vol 14 (5) ◽  
pp. 939-948 ◽  
Author(s):  
Lei ZHANG ◽  
Qi-sheng ZUO ◽  
Dong LI ◽  
Chao LIAN ◽  
Kamel E Ahmed ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Spermatogonial Stem Cells ◽  
Rna Seq ◽  
Stat Signaling

scholarly journals Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

2020 ◽  
Vol 21 (4) ◽  
pp. 1377
Author(s):  
Pavan Kumar Dhanyamraju ◽  
Soumya Iyer ◽  
Gayle Smink ◽  
Yevgeniya Bamme ◽  
Preeti Bhadauria ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Lymphoblastic Leukemia ◽  
Regulatory Elements ◽  
Binding Motif ◽  
Functional Inactivation

Regulation of oncogenic gene expression by transcription factors that function as tumor suppressors is one of the major mechanisms that regulate leukemogenesis. Understanding this complex process is essential for explaining the pathogenesis of leukemia as well as developing targeted therapies. Here, we provide an overview of the role of Ikaros tumor suppressor and its role in regulation of gene transcription in acute leukemia. Ikaros (IKZF1) is a DNA-binding protein that functions as a master regulator of hematopoiesis and the immune system, as well as a tumor suppressor in acute lymphoblastic leukemia (ALL). Genetic alteration or functional inactivation of Ikaros results in the development of high-risk leukemia. Ikaros binds to the specific consensus binding motif at upstream regulatory elements of its target genes, recruits chromatin-remodeling complexes and activates or represses transcription via chromatin remodeling. Over the last twenty years, a large number of Ikaros target genes have been identified, and the role of Ikaros in the regulation of their expression provided insight into the mechanisms of Ikaros tumor suppressor function in leukemia. Here we summarize the role of Ikaros in the regulation of the expression of the genes whose function is critical for cellular proliferation, development, and progression of acute lymphoblastic leukemia.

scholarly journals TGF-β Signaling and the Epithelial-Mesenchymal Transition during Palatal Fusion

2018 ◽  
Vol 19 (11) ◽  
pp. 3638 ◽  
Author(s):  
Akira Nakajima ◽  
Charles F. Shuler ◽  
Alexander Gulka ◽  
Jun-ichi Hanai
Keyword(s):  
Cell Fate ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Genetically Engineered ◽  
Fusion Process ◽  
Mesenchymal Transition ◽  
Morphological Process ◽  
Palatal Fusion ◽  
Genetically Engineered Mice

Signaling by transforming growth factor (TGF)-β plays an important role in development, including in palatogenesis. The dynamic morphological process of palatal fusion occurs to achieve separation of the nasal and oral cavities. Critically and specifically important in palatal fusion are the medial edge epithelial (MEE) cells, which are initially present at the palatal midline seam and over the course of the palate fusion process are lost from the seam, due to cell migration, epithelial-mesenchymal transition (EMT), and/or programed cell death. In order to define the role of TGF-β signaling during this process, several approaches have been utilized, including a small interfering RNA (siRNA) strategy targeting TGF-β receptors in an organ culture context, the use of genetically engineered mice, such as Wnt1-cre/R26R double transgenic mice, and a cell fate tracing through utilization of cell lineage markers. These approaches have permitted investigators to distinguish some specific traits of well-defined cell populations throughout the palatogenic events. In this paper, we summarize the current understanding on the role of TGF-β signaling, and specifically its association with MEE cell fate during palatal fusion. TGF-β is highly regulated both temporally and spatially, with TGF-β3 and Smad2 being the preferentially expressed signaling molecules in the critical cells of the fusion processes. Interestingly, the accessory receptor, TGF-β type 3 receptor, is also critical for palatal fusion, with evidence for its significance provided by Cre-lox systems and siRNA approaches. This suggests the high demand of ligand for this fine-tuned signaling process. We discuss the new insights in the fate of MEE cells in the midline epithelial seam (MES) during the palate fusion process, with a particular focus on the role of TGF-β signaling.

scholarly journals A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis

2019 ◽  
Vol 116 (48) ◽  
pp. 24184-24195 ◽  
Author(s):  
Iacovos P. Michael ◽  
Sadegh Saghafinia ◽  
Douglas Hanahan
Keyword(s):  
Tumor Growth ◽  
Target Genes ◽  
Genetically Engineered ◽  
Malignant Progression ◽  
Metastasis Suppressor ◽  
Invasion And Metastasis ◽  
Biologically Relevant ◽  
Genetically Engineered Mouse Model ◽  
Functional Involvement

MicroRNA-mediated gene regulation has been implicated in various diseases, including cancer. This study examined the role of microRNAs (miRNAs) during tumorigenesis and malignant progression of pancreatic neuroendocrine tumors (PanNETs) in a genetically engineered mouse model. Previously, a set of miRNAs was observed to be specifically up-regulated in a highly invasive and metastatic subtype of mouse and human PanNET. Using functional assays, we now implicate different miRNAs in distinct phenotypes: miR-137 stimulates tumor growth and local invasion, whereas the miR-23b cluster enables metastasis. An algorithm, Bio-miRTa, has been developed to facilitate the identification of biologically relevant miRNA target genes and applied to these miRNAs. We show that a top-ranked miR-137 candidate gene, Sorl1, has a tumor suppressor function in primary PanNETs. Among the top targets for the miR-23b cluster, Acvr1c/ALK7 has recently been described to be a metastasis suppressor, and we establish herein that it is down-regulated by the miR-23b cluster, which is crucial for its prometastatic activity. Two other miR-23b targets, Robo2 and P2ry1, also have demonstrable antimetastatic effects. Finally, we have used the Bio-miRTa algorithm in reverse to identify candidate miRNAs that might regulate activin B, the principal ligand for ALK7, identifying thereby a third family of miRNAs—miRNA-130/301—that is congruently up-regulated concomitant with down-regulation of activin B during tumorigenesis, suggestive of functional involvement in evasion of the proapoptotic barrier. Thus, dynamic up-regulation of miRNAs during multistep tumorigenesis and malignant progression serves to down-regulate distinctive suppressor mechanisms of tumor growth, invasion, and metastasis.

TCF: Lady Justice Casting the Final Verdict on the Outcome of Wnt Signalling

2002 ◽  
Vol 383 (2) ◽  
pp. 255-261 ◽  
Author(s):  
H. Brantjes ◽  
N. Barker ◽  
J. van Es ◽  
H. Clevers
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Signal Transduction Pathway ◽  
Wnt Signalling ◽  
Early Event ◽  
Embryonic Patterning ◽  
Repressor Proteins ◽  
Downstream Effectors ◽  
Signalling Cascade

Abstract The Wnt signalling cascade plays an important role during embryonic patterning and cell fate determination and is highly conserved throughout evolution. Factors of the TCF/LEF HMG domain family (Tcfs) are the downstream effectors of this signal transduction pathway. Upon Wnt signalling, a cascade is initiated that results in the translocation of βcatenin to the nucleus, where it interacts with Tcf to generate a transcriptionally active complex. This bipartite transcription factor is targeted to the upstream regulatory regions of Tcf target genes. In the absence of Wnt signals, βcatenin is degraded in the cytoplasm via the ubiquitinproteasome pathway. Several proteins are instrumental in achieving this tight regulation of βcatenin levels in the cell, including adenomatous polyposis coli (APC), GSK3 β, and Axin/Conductin. Deregulation of the Wnt signalling pathway is implicated in several forms of cancer, such as colon carcinoma and melanoma. This deregulation is achieved via mutation of APC, βcatenin or Axin, resulting in elevated βcatenin levels and the presence of constitutively active Tcfβcatenin complexes in the nucleus. The accompanying inappropriate activation of target genes is considered to be a critical, early event in this carcinogenesis. In addition to regulating βcatenin levels, normal healthy cells have evolved a second level of regulation, by manipulating the activity of the Tcf proteins themselves. In the absence of Wnt signalling, Tcf complexes with several transcriptional repressor proteins ensuring active repression of Tcf target genes. In this review the dual role of Tcf proteins in the Wnt signalling cascade will be discussed.

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