scholarly journals Wingless promotes JNK/MMPs positive feedback loop mediate tumour microtubes expansion, glioma progression and neurodegeneration

2019 ◽  
Author(s):  
Marta Portela ◽  
Natasha Fahey-Lozano ◽  
Sergio Casas-Tintó
Keyword(s):  
Glial Cells ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Matrix Metalloproteases ◽  
Positive Feedback Loop ◽  
Mediate Cell ◽  
Cellular Feature ◽  
The Brain

SummaryGlial cells display a network of projections (cytonemes) which mediate cell to cell communication. Under pathological conditions like glioblastoma (GB), cytonemes transform into ultra-long tumour microtubes (TMs). These filopodia infiltrate through the brain, enwrap neurons and deplete wingless (Wg)/WNT, as a consequence GB progress and neurons undergo synapse loss and degeneration. Thus TMs emerge as a central cellular feature of GB which correlates with a poor prognosis in patients and animal models. Here we describe in a Drosophila model for GB the molecular mechanisms behind TMs production, infiltration and maintenance. Glial cells are initially transformed into malignant GB upon EGFR and PI3K pathways constitutive activation, afterwards GB cells establish a positive feedback loop including Wg signalling, JNK and matrix metalloproteases (MMP). In order, Frizzled1 mediates Wg signalling upregulation which activates JNK in GB. As a consequence, MMPs are upregulated and facilitate TMs infiltration in the brain, hence GB TMs network expands and mediate further wingless depletion to close the loop.

scholarly journals Mathematical modelling of diurnal regulation of carbohydrate allocation by osmo-related processes in plants

2015 ◽  
Vol 12 (104) ◽  
pp. 20141357 ◽  
Author(s):  
Alexandra Pokhilko ◽  
Oliver Ebenhöh
Keyword(s):  
Mathematical Model ◽  
Mathematical Modelling ◽  
Growth Regulator ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Positive Feedback Loop ◽  
Sink Demand ◽  
Sucrose Supply ◽  
Diurnal Regulation

Plants synthesize sucrose in source tissues (mainly mature leafs) and supply it for growth of sink tissues (young leafs). Sucrose is derived from photosynthesis during daytime and from starch at night. Because the diurnal regulation of sucrose fluxes is not completely understood, we built a mathematical model designed to reproduce all key experimental observations. For this, assumptions were made about the molecular mechanisms underlying the regulations, which are all motivated by experimental facts. The key regulators in our model are two kinases (SnRK1 and osmo-sensitive kinase OsmK) under the control of the circadian clock. SnRK1 is activated in the night to prepare for regularly occurring carbon-limiting conditions, whereas OsmK is activated during the day to prepare for water deficit, which often occurs in the afternoon. Decrease of SnRK1 and increase of OsmK result in partitioning of carbon towards sucrose to supply growing sink tissues. Concomitantly, increasing levels of the growth regulator trehalose-6-phosphate stimulates the development of new sink tissues and thus sink demand, which further activates sucrose supply in a positive feedback loop. We propose that OsmK acts as a timer to measure the length of the photoperiod and suggest experiments how this hypothesis can be validated.

scholarly journals A positive feedback loop between glial cells missing 1 (GCM1) and human chorionic gonadotropin (hCG) regulates placental hCGβ expression and cell differentiation

2015 ◽  
pp. MCB.00655-15 ◽  
Author(s):  
Mei-Leng Cheong ◽  
Liang-Jie Wang ◽  
Pei-Yun Chuang ◽  
Ching-Wen Chang ◽  
Yun-Shien Lee ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Fusion ◽  
Glial Cells ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Target Genes ◽  
Positive Feedback Loop ◽  
Α Subunit

Human chorionic gonadotropin (hCG) is composed of a common α subunit and a placenta-specific β subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cAMP. Although the ubiquitous AP2 transcription factors, TFAP2A and TFAP2C, may regulate hCGβ expression, it remains unclear how cAMP stimulates placenta-specific hCGβ gene expression and trophoblastic differentiation. Here we demonstrated that the placental Glial Cells Missing 1 (GCM1) transcription factor binds to a highly conserved promoter region in all the six hCGβ paralogues by ChIP-chip analysis. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate hCGβ promoter through a GCM1-binding site (GBS1), which also constitutes a previously-identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between hCGβ promoter and GCM1, but not TFAP2C. Indeed, the hCG-cAMP-PKA signaling pathway also stimulates Ser269 and Ser275 phosphorylation in GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the syncytin-1 fusogenic protein, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCGβ expression and cell differentiation.

scholarly journals A Positive Feedback Loop of lncRNA-RMRP/ZNRF3 axis and Wnt/β-catenin Signaling Regulates Temozolomide Resistance in Glioma

2020 ◽  
Author(s):  
Tie Liu ◽  
Jie Hu ◽  
Bo Han ◽  
Shishan Tan ◽  
Wenqing Jia ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Mrna Stability ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Positive Feedback Loop ◽  
Protein Levels ◽  
Glioma Xenograft ◽  
Rna Immunoprecipitation

Abstract Background: Drug resistance strikingly limits the therapeutic effect of temozolomide (TMZ) (a common drug for glioma). Long non-coding RNA (lncRNA) RMRP was found to be implicated in glioma progression. However, the effects of RMRP on TMZ resistance along with related molecular mechanisms are poor defined in glioma. Methods: RMRP, ZNRF3, and IGF2BP3 were screened out by bioinformatics analysis. The expression levels of lncRNAs and mRNAs were measured by RT-qPCR assay. Protein levels of genes were detected by western blot and immunofluorescence assays. ZNRF3 mRNA stability was analyzed using Actinomycin D assay. Cell proliferative ability and survival rate were determined by CCK-8 assay. Cell apoptotic patterns were estimated by flow cytometry. The effects of RMRP knockdown on the growth of TMZ-treated glioma xenograft tumors were explored in vivo. The relationships among IGF2BP3, RMRP and ZNRF3 were explored by bioinformatics prediction analysis, RNA immunoprecipitation and RNA pull-down assays. Results: RMRP was highly expressed in glioma. RMRP knockdown curbed cell proliferation, facilitated cell apoptosis and reduced TMZ resistance in glioma cells and hindered the growth of TMZ-treated glioma xenograft tumors. RMRP exerted its functions by down-regulating ZNRF3 in glioma cells. IGF2BP3 interacted with RMRP and ZNRF3 mRNA. RMRP reduced ZNRF3 expression and mRNA stability by IGF2BP3. RMRP knockdown inhibited β-catenin expression by up-regulating ZNRF3 and β-catenin promoted RMRP expression in glioma cells. Conclusion: RMRP/ZNRF3 axis and Wnt/β-catenin signaling formed a positive feedback loop to regulate TMZ resistance in glioma. The sustained activation of Wnt/β-catenin signaling by RMRP contributes the better management of cancers.

scholarly journals Cell to cell communication is an early event in glioblastoma

2020 ◽  
Author(s):  
Marta Portela ◽  
Teresa Mitchell ◽  
Sergio Casas-Tintó
Keyword(s):  
Cell Communication ◽  
Matrix Metalloproteases ◽  
Temporal Organization ◽  
Early Event ◽  
Cellular Interactions ◽  
Jnk Pathway ◽  
The Central Nervous System ◽  
Mediate Cell ◽  
Molecular Signals ◽  
The Brain

SummaryGlioblastoma (GB) is the most aggressive and lethal tumour of the central nervous system (CNS). GB cells proliferate rapidly and display a network of ultra-long tumour microtubes (TMs) that mediate cell to cell communication. GB TMs infiltrate into the brain, enwrap neurons and facilitate the depletion of Wingless (Wg)/WNT from the neighbouring neurons. GB cells establish a positive feedback loop including Wg signalling upregulation that activates the JNK pathway and matrix metalloproteases (MMPs), in turn, these signals promote TMs infiltration, GB progression and neuronal synapse loss and degeneration. Thus, cellular and molecular signals other than primary mutations emerge as central players of GB. Here we describe the temporal organization of the events that occur in GB. We define the progressive activation of JNK pathway signalling mediated by Grindelwald (Grnd) receptor, is caused by the ligand Eiger (Egr)/TNFα produced by the healthy tissue. We propose that cellular interactions of GB with the rest of the brain is an early event that precedes GB proliferation and expansion. We conclude that non-autonomous signals facilitate GB progression and contribute to the complexity and versatility of these incurable tumours.

scholarly journals A positive feedback loop of lncRNA-RMRP/ZNRF3 axis and Wnt/β-catenin signaling regulates the progression and temozolomide resistance in glioma

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Tie Liu ◽  
Jie Hu ◽  
Bo Han ◽  
Shishan Tan ◽  
Wenqing Jia ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Mrna Stability ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Positive Feedback Loop ◽  
Argonaute 2 ◽  
Protein Levels ◽  
Glioma Xenograft

AbstractDrug resistance strikingly limits the therapeutic effect of temozolomide (TMZ) (a common drug for glioma). Long non-coding RNA (lncRNA) RMRP has been found to be implicated in glioma progression. However, the effect of RMRP on TMZ resistance along with related molecular mechanisms is poorly defined in glioma. In the present study, RMRP, ZNRF3, and IGF2BP3 were screened out by bioinformatics analysis. The expression levels of lncRNAs and mRNAs were measured by RT-qPCR assay. Protein levels of genes were detected by western blot and immunofluorescence assays. ZNRF3 mRNA stability was analyzed using Actinomycin D assay. Cell proliferative ability and survival rate were determined by CCK-8 assay. Cell apoptotic pattern was estimated by flow cytometry. The effect of RMRP knockdown on the growth of TMZ-treated glioma xenograft tumors was explored in vivo. The relationships of IGF2BP3, RMRP, and ZNRF3 were explored by bioinformatics prediction analysis, RNA immunoprecipitation, luciferase, and RNA pull-down, and chromatin immunoprecipitation assays. The results showed that RMRP was highly expressed in glioma. RMRP knockdown curbed cell proliferation, facilitated cell apoptosis and reduced TMZ resistance in glioma cells, and hindered the growth of TMZ-treated glioma xenograft tumors. RMRP exerted its functions by down-regulating ZNRF3 in glioma cells. IGF2BP3 interacted with RMRP and ZNRF3 mRNA. IGF2BP3 knockdown weakened the interaction of Argonaute 2 (Ago2) and ZNRF3. RMRP reduced ZNRF3 expression and mRNA stability by IGF2BP3. RMRP knockdown inhibited β-catenin expression by up-regulating ZNRF3. The inhibition of Wnt/β-catenin signaling pathway by XAV-939 weakened RMRP-mediated TMZ resistance in glioma cells. β-catenin promoted RMRP expression by TCF4 in glioma cells. In conclusion, RMRP/ZNRF3 axis and Wnt/β-catenin signaling formed a positive feedback loop to regulate TMZ resistance in glioma. The sustained activation of Wnt/β-catenin signaling by RMRP might contribute to the better management of cancers.

scholarly journals Citrus PH4–Noemi regulatory complex is involved in proanthocyanidin biosynthesis via a positive feedback loop

2019 ◽  
Vol 71 (4) ◽  
pp. 1306-1321 ◽  
Author(s):  
Yin Zhang ◽  
Junli Ye ◽  
Chaoyang Liu ◽  
Qiang Xu ◽  
Lichang Long ◽  
...  
Keyword(s):  
Fruit Quality ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Citrus Fruit ◽  
Wild Type ◽  
Biosynthetic Genes ◽  
Positive Feedback Loop ◽  
Regulatory Complex ◽  
In The Wild

Abstract Proanthocyanidins (PAs; or condensed tannins) are a major class of flavonoids that contribute to citrus fruit quality. However, the molecular mechanism responsible for PA biosynthesis and accumulation in citrus remains unclear. Here, we identify a PH4–Noemi regulatory complex that regulates proanthocyanidin biosynthesis in citrus. Overexpression of PH4 or Noemi in citrus calli activated the expression of PA biosynthetic genes and significantly increased the PA content. Interestingly, Noemi was also shown to be up-regulated in CsPH4-overexpressing lines compared with wild-type calli. Simultaneously, CsPH4 partially complemented the PA-deficient phenotype of the Arabidopsis tt2 mutant and promoted PA accumulation in the wild-type. Further analysis revealed that CsPH4 interacted with Noemi, and together these proteins synergistically activated the expression of PA biosynthetic genes by directly binding to the MYB-recognizing elements (MRE) of the promoters of these genes. Moreover, CsPH4 could directly bind to the promoter of Noemi and up-regulate the expression of this gene. These findings explain how the CsPH4–Noemi regulatory complex contributes to the activation of PA biosynthetic genes via a positive feedback loop and provide new insights into the molecular mechanisms underlying PA biosynthesis, which can be effectively employed for metabolic engineering to improve citrus fruit quality.

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