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.

scholarly journals CircCNTNAP3-TP53-positive feedback loop suppresses malignant progression of esophageal squamous cell carcinoma

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Hui Wang ◽  
Xuming Song ◽  
Yajing Wang ◽  
Xuewen Yin ◽  
Yingkuan Liang ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Malignant Progression ◽  
Gene Transcript ◽  
Wild Type ◽  
Positive Feedback Loop

AbstractMutation or downregulation of p53 (encoded by TP53) accelerates tumorigenesis and malignant progression in esophageal squamous cell carcinoma (ESCC). However, it is still unknown whether circular RNAs (circRNAs), a novel class of endogenous noncoding RNAs, participate in the regulation of this progress. In this study, we explored the expression profiles of circRNAs in three paired samples of ESCC and identified cCNTNAP3, which is a circRNA that originates from the CNTNAP3 gene transcript and is highly expressed in normal human esophageal tissue. However, we found that the cCNTNAP3 expression level was significantly downregulated in ESCC tissues. In vitro and in vivo studies revealed that cCNTNAP3 inhibited proliferation and increased apoptosis in p53 wild-type ESCC cells, but not in mutant cells. Mechanistically, we found that cCNTNAP3 promotes the expression of p53 by sponging miR-513a-5p. Rescue assay confirmed that the suppressive function of cCNTNAP3 was dependent on miR-513a-5p. We also observed that p53/RBM25 participated in the formation of cCNTNAP3, which implied the existence of a positive feedback loop between cCNTNAP3 and p53. Furthermore, the downregulation of cCNTNAP3 was significantly correlated with later T stage and thus can serve as an independent risk factor for the overall survival of patients with p53 wild-type ESCC. In conclusion, the cCNTNAP3-TP53 positive feedback loop may provide a potential target for the management of ESCC, which also reveals the important role of circRNAs in the regulation of p53.

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 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 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 T-β-MCA Regulates the Termination of Liver Regeneration via the P53/miR-34a/SIRT1 Positive Feedback Loop by Suppressing the FXR/SHP Signaling Pathway.

2020 ◽  
Author(s):  
Fangchao Yuan ◽  
Yao Chen ◽  
Hao Wu ◽  
Minghua Cong ◽  
Menghao Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Liver Regeneration ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Late Phase ◽  
Liver Weight ◽  
Wild Type ◽  
Positive Feedback Loop ◽  
And Function ◽  
Shed Light

Abstract Background The capacity of the liver to restore its architecture and function assures good prognoses of patients who suffer serious hepatic injury or cancer resection. In our previous study, we initially found that the P53/miR-34a/SIRT1 positive feedback loop has a remarkable negative regulatory effect, which is related to the termination of liver regeneration. Here, we described how P53/miR-34a/SIRT1 positive feedback loop controls liver regeneration and its possible relationship with liver cancer.Method We performed partial hepatectomy (PH) in mice transfected with adenovirus (Ade) overexpressing P53 and adenovirus-associated virus (AAV) knock-downing miR-34a. LR was analyzed by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were investigated. Bile acid (BA) levels during LR were analyzed by metabolomics of bile acids. Results We found that the P53/miR-34a/SIRT1 positive feedback loop was activated in the late phase of LR. Overexpression of P53 terminated LR early and enhanced P53/miR-34a/SIRT1 positive feedback loop expression and its proapoptotic effect. Mice from the Ade-P53 group showed smaller livers and higher levels of serum ALT and AST than control mice. While knock-down of miR-34a abolished P53/miR-34a/SIRT1 positive feedback loop during LR. Mice from anti-miR-34a group showed larger livers and lower levels of PCNA-positive cells than control mice. T-β-MCA increased gradually during LR and peaked at 7 days after PH. T-β-MCA inhibited cell proliferation and promoted cell apoptosis via facilitating the P53/miR-34a/SIRT1 positive feedback loop during LR by suppressing FXR/SHP. Conclusion The P53/miR-34a/SIRT1 positive feedback loop plays an important role in the termination of LR. Our findings shed light on the molecular and metabolic mechanisms of LR termination and provide a potential therapeutic alternative for treating P53-wild-type HCC patients.

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.

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