Abstract 16626: Endothelial Zinc Transporter Zip8 Regulates Ventricular Trabeculation and Compaction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jihyun Jang ◽  
Deqiang Li
Keyword(s):  
Notch Signaling ◽  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Zinc Transporter ◽  
Late Gestation ◽  
Downstream Target ◽  
Conditional Deletion ◽  
Developing Heart ◽  
Morphogenetic Protein ◽  
Downstream Target Gene

Trabeculation and subsequent compaction of the ventricular wall are essential for normal heart morphogenesis. In human, excessive trabeculation and impaired myocardial compaction during earlyheart development lead to left ventricular non compaction (LVNC), a third most common cardiomyopathies after dilated and hypertrophic cardiomyopathies. LVNC is also associated with cardiac arrhythmia and sudden cardiac death. The etiology of LVNC is poorly understood. Recently our group identified that Zip8, a Zinc transporter, implicated in ventricular trabeculation and compaction (JCI, 2018,PMID: 29337306). However, it remains elusive how Zip8 regulates these processes through cellular and molecular mechanisms. We conditionally ablated Zip8 in the endothelial cells, epicardial cells and cardiomyocytes in the developing heart respectively. Strikingly, deletion of Zip8 in the endothelial cellsgave rise to LVNC phenotypes, identical to cardiac phenotypes from the global Zip8 knockouts. Incontrast, hearts with deletions of Zip8 in either epicardium or myocardium developed normally. Further,we found only conditional deletion of Zip8 in the endothelium in the early developing hearts (at E8.5)generated LVNC but not in the late gestation stage (E13.5), suggesting that Zip8 plays critical roles during the initial trabeculation stage. Interestingly, we found that endocardial Zip8 deficiency resulted inthe upregulation of Notch signaling, as evidenced by the increase of intracellular domain of notch protein(NICD) and its downstream target gene, bone morphogenetic protein 10 (BMP10). When the notch signaling is inhibited in the endothelial Zip8 knockout hearts either by DAPI, a γ secretase inhibitor, or by genetic deletion of Rbpj, the LVNC cardiac phenotypes are partially rescued. These results suggest thatZip8 orchestrates myocardial trabeculation and compaction by regulating notch signaling.Collectively, our study provides novel insights into the mechanisms of LVNC, suggesting that genetic mutations in Zip8 or zinc deficiency may contribute to LNVC in humans.

scholarly journals LINC00261 Suppresses Cisplatin Resistance of Esophageal Squamous Cell Carcinoma Through miR-545-3p/MT1M Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Lijun Wang ◽  
Xiaojun Wang ◽  
Pengwei Yan ◽  
Yatian Liu ◽  
Xuesong Jiang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Cure Rate ◽  
Downstream Target ◽  
Downstream Target Gene ◽  
Non Coding Rnas ◽  
New Treatment

To improve the survival rate and cure rate of patients, it is necessary to find a new treatment scheme according to the molecular composition of (ESCC) in esophageal squamous cell carcinoma. Long non-coding RNAs (lncRNAs) regulate the progression of ESCC by various pathophysiological pathways. We explored the possible function of the lncRNA LINC00261 (LINC00261) on cisplatin (DDP) resistance of ESCC and its relative molecular mechanisms. In the study, we found that LINC00261 was downregulated in ESCC tissues, cell lines, and DDP-resistant ESCC patients. Besides, overexpression of LINC00261 not only inhibited cell proliferation, and DDP resistance but also promotes cell apoptosis. Further mechanistic research showed that LINC00261 sponged miR-545-3p which was negatively correlated with the expression of LINC00261. In addition, functional experiments revealed that upregulation of miR-766-5p promoted proliferation and enhanced DDP resistance. Subsequently, MT1M was testified to be the downstream target gene of miR-545-3p. Rescue experiments revealed that overexpression of MT1M largely restores miR-545-3p mimics-mediated function on ESCC progression. Our results demonstrate that the LINC00261 suppressed the DDP resistance of ESCC through miR-545-3p/MT1M axis.

scholarly journals Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism

2020 ◽  
Author(s):  
Victoria L. Castro ◽  
Nayeli G. Reyes-Nava ◽  
Brianna B. Sanchez ◽  
Cesar G. Gonzalez ◽  
Anita M. Quintana
Keyword(s):  
Wnt Signaling ◽  
Cholesterol Synthesis ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Neural Crest Cell ◽  
Craniofacial Development ◽  
Inborn Errors ◽  
Downstream Target ◽  
Downstream Target Gene ◽  
Craniofacial Defects

AbstractBackgroundInborn errors of cholesterol metabolism occur as a result of mutations in the cholesterol synthesis pathway (CSP). Although mutations in the CSP cause a multiple congenital anomaly syndrome, craniofacial abnormalities are a hallmark phenotype associated with these disorders. Previous studies have established that mutation of the zebrafish hmgcs1 gene (Vu57 allele), which encodes the first enzyme in the CSP, causes defects in craniofacial development and abnormal neural crest cell (NCC) differentiation. However, the molecular mechanisms by which the products of the CSP disrupt NCC differentiation are not completely known. Cholesterol is known to regulate the activity of WNT signaling, an established regulator of NCC differentiation. We hypothesized that defects in cholesterol synthesis reduce WNT signaling, consequently resulting in abnormal craniofacial development.MethodsTo test our hypothesis we performed a combination of pharmaceutical inhibition, gene expression assays, and targeted rescue experiments to understand the function of CSP and WNT signaling during craniofacial development.ResultsWe demonstrate reduced expression of axin2, a WNT downstream target gene in homozygous carriers of the Vu57 allele and in larvae treated with Ro-48-8071, which inhibits the synthesis of cholesterol. Moreover, activation of WNT signaling via treatment with a WNT agonist completely restored the craniofacial defects present in the Vu57 allele.ConclusionsCollectively, these data suggest interplay between the CSP and WNT signaling during craniofacial development.

scholarly journals Neddylation mediates ventricular chamber maturation through repression of Hippo signaling

2018 ◽  
Vol 115 (17) ◽  
pp. E4101-E4110 ◽  
Author(s):  
Jianqiu Zou ◽  
Wenxia Ma ◽  
Jie Li ◽  
Rodney Littlejohn ◽  
Hongyi Zhou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Development ◽  
Molecular Mechanisms ◽  
Heart Defects ◽  
Left Ventricular ◽  
Late Gestation ◽  
Hippo Signaling ◽  
Cardiomyocyte Proliferation ◽  
Ventricular Noncompaction ◽  
Cullin 7

During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2-E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP-deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling.

scholarly journals Pendrin Is a Novel In Vivo Downstream Target Gene of the TTF-1/Nkx-2.1 Homeodomain Transcription Factor in Differentiated Thyroid Cells

2005 ◽  
Vol 25 (22) ◽  
pp. 10171-10182 ◽  
Author(s):  
Monica Dentice ◽  
Cristina Luongo ◽  
Antonia Elefante ◽  
Raffaele Ambrosio ◽  
Salvatore Salzano ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Homeobox Gene ◽  
Dominant Negative ◽  
Specific Gene ◽  
Thyroid Cells ◽  
Downstream Target ◽  
C Terminus ◽  
Downstream Target Gene

ABSTRACT Thyroid transcription factor gene 1 (TTF-1) is a homeobox-containing gene involved in thyroid organogenesis. During early thyroid development, the homeobox gene Nkx-2.5 is expressed in thyroid precursor cells coincident with the appearance of TTF-1. The aim of this study was to investigate the molecular mechanisms underlying thyroid-specific gene expression. We show that the Nkx-2.5 C terminus interacts with the TTF-1 homeodomain and, moreover, that the expression of a dominant-negative Nkx-2.5 isoform (N188K) in thyroid cells reduces TTF-1-driven transcription by titrating TTF-1 away from its target DNA. This process reduced the expression of several thyroid-specific genes, including pendrin and thyroglobulin. Similarly, down-regulation of TTF-1 by RNA interference reduced the expression of both genes, whose promoters are sensitive to and directly associate with TTF-1 in the chromatin context. In conclusion, we demonstrate that pendrin and thyroglobulin are downstream targets in vivo of TTF-1, whose action is a prime factor in controlling thyroid differentiation in vivo.

scholarly journals Long intergenic non-coding RNA 00473 promotes proliferation and migration of gastric cancer via the miR-16-5p/CCND2 axis and by regulating AQP3

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Shuaishuai Zhuo ◽  
Miaomiao Sun ◽  
Rumeng Bai ◽  
Die Lu ◽  
Shihao Di ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Western Blot ◽  
Molecular Mechanisms ◽  
Downstream Target ◽  
Non Coding Rna ◽  
Downstream Target Gene ◽  
Proliferation And Metastasis ◽  
And Migration

AbstractGastric cancer (GC) is one of the most common malignancies worldwide, but its molecular mechanisms remain unclear. Increasing evidence indicates that long non-coding RNAs (LncRNAs) play a pivotal role in various cancers recently. Our present study focused on exploring the function of long intergenic non-coding RNA 00473 (LINC00473) in GC. In this study, we found that LINC00473 expression was aberrantly increased in tumor tissues compared with the paired para-cancerous tissues. The expression of high LINC00473 in GC was notably correlated with a higher risk of lymphatic metastasis, a higher incidence of vascular cancer embolus, and advanced TNM stage. Further experiments showed that the overexpression of LINC00473 could promote the proliferation and metastasis of GC cells both in vitro and in vivo. The apoptosis of GC cells increased significantly by the decrease of LINC00473. Mechanistically, LINC00473 could sponge miR-16-5p in the cytoplasm and relieve its suppression of CCND2. Moreover, AQP3 was found to be a significant downstream target gene for LINC00473 through RNA transcriptome sequencing, as demonstrated by qRT-PCR and western blot. Overexpression of LINC00473 can partially reverse the effects of AQP3 decrease on GC proliferation and metastasis. LINC00473 regulated AQP3 expression through CREB was confirmed by western blot. Our research indicates that LINC00473/miR-16-5p/CCND2 axis plays a role in the proliferation of GC and modulates AQP3 to influence GC cell metastasis, making it a potential therapeutic target for GC.

scholarly journals A Novel Identified Long Non-coding RNA, lncRNA MEF2C-AS1, Inhibits Cervical Cancer via Regulation of miR-592/RSPO1

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoping Wang ◽  
Changhong Zhang ◽  
Meixuan Gong ◽  
Chen Jiang
Keyword(s):  
Cervical Cancer ◽  
Molecular Mechanisms ◽  
Survival Curve ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Downstream Target ◽  
Qrt Pcr ◽  
Kaplan Meier ◽  
Downstream Target Gene

Purpose: Our purpose was to investigate the effect of lncRNA MEF2C antisense RNA 1 (MEF2C-AS1) on cervical cancer and further explore its underlying molecular mechanisms.Methods: The proliferation, migration and invasion of CC cells were determined by counting Kit-8 (CCK-8), colony formation assay, and transwell assays, respectively. qRT-PCR and western blot were conducted to quantitatively detect the expression of lncRNA MEF2C-AS1, miR-592 and R-spondin1 (RSPO1). Kaplan-Meier survival curve from the Cancer Genome Atlas (TCGA) database and the Gene Expression Profiling Interactive Analysis (GEPIA) website was used to describe the overall survival. Bioinformatics analysis was performed to search the downstream target of lncRNA MEF2C-AS1 and miR-592. Luciferase reporter assay was conducted to detect the interaction between lncRNA MEF2C-AS1 and miR-592 or miR-592 and RSPO1.Results: The data from GEPIA website showed that lncRNA MEF2C-AS1 expression was down-regulated in CC tissues and also associated with survival rate of CC patients. Moreover, the results of qRT-PCR also showed lncRNA MEF2C-AS1 was lowly expressed in CC cells. Subsequently, we confirmed that overexpression of lncRNA MEF2C-AS1 inhibited the proliferation, migration and invasion of CC cells. Further research illustrated that lncRNA MEF2C-AS1 was the target of miR-592, and RSPO1 was the downstream target gene of miR-592. Importantly, functional research findings indicated that lncRNA MEF2C-AS1 inhibited CC via suppressing miR-592 by targeting RSPO1.Conclusion: In our study, we demonstrated the functional role of the lncRNA MEF2C-AS1-miR-592-RSPO1 axis in the progression of CC, which provides a latent target for CC treatment.

scholarly journals RIP1 Perturbation Induces Chondrocyte Necroptosis and Promotes Osteoarthritis Pathogenesis via Targeting BMP7

2021 ◽  
Vol 9 ◽  
Author(s):  
Jin Cheng ◽  
Xiaoning Duan ◽  
Xin Fu ◽  
Yanfang Jiang ◽  
Peng Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cartilage Degradation ◽  
Vital Role ◽  
Interacting Protein ◽  
Downstream Target ◽  
Disease Modifying Therapy ◽  
Morphogenetic Protein ◽  
Joint Disorder

Osteoarthritis (OA) is a highly prevalent and debilitating joint disorder that characterized by progressive destruction of articular cartilage. There is no effective disease-modifying therapy for the condition due to limited understanding of the molecular mechanisms on cartilage maintenance and destruction. Receptor-interacting protein kinase 1 (RIP1)-mediated necroptosis plays a vital role in various diseases, but the involvement of RIP1 in OA pathogenesis remains largely unknown. Here we show that typical necrotic cell morphology is observed within human OA cartilage samples in situ, and that RIP1 is significantly upregulated in cartilage from both OA patients and experimental OA rat models. Intra-articular RIP1 overexpression is sufficient to induce structural and functional defects of cartilage in rats, highlighting the crucial role of RIP1 during OA onset and progression by mediating chondrocyte necroptosis and disrupting extracellular matrix (ECM) metabolism homeostasis. Inhibition of RIP1 activity by its inhibitor necrostatin-1 protects the rats from trauma-induced cartilage degradation as well as limb pain. More importantly, we identify bone morphogenetic protein 7 (BMP7) as a novel downstream target that mediates RIP1-induced chondrocyte necroptosis and OA manifestations, thereby representing a non-canonical regulation mode of necroptosis. Our study supports a model whereby the activation of RIP1-BMP7 functional axis promotes chondrocyte necroptosis and subsequent OA pathogenesis, thus providing a new therapeutic target for OA.

The Regulation of Downstream Target Gene AP-2γ by Transcription Factor OCT-4

2013 ◽  
Vol 40 (1) ◽  
pp. 43
Author(s):  
Xiao-Meng ZHAO ◽  
Cheng WANG ◽  
Xiao-Feng LI ◽  
Xiao-Ting ZHANG ◽  
Xi-Zhi LIU ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Gene ◽  
Downstream Target ◽  
Downstream Target Gene

Aryl Hydrocarbon Receptor: Its Regulation and Roles in Transformation and Tumorigenesis

2019 ◽  
Vol 20 (6) ◽  
pp. 625-634 ◽  
Author(s):  
Xun Che ◽  
Wei Dai
Keyword(s):  
Target Gene ◽  
Tumor Development ◽  
Environmental Response ◽  
Carcinogenic Effect ◽  
Post Translational Modifications ◽  
Downstream Target ◽  
Aryl Hydrocarbon ◽  
Downstream Target Gene ◽  
Major Mediator

AhR is an environmental response gene that mediates cellular responses to a variety of xenobiotic compounds that frequently function as AhR ligands. Many AhR ligands are classified as carcinogens or pro-carcinogens. Thus, AhR itself acts as a major mediator of the carcinogenic effect of many xenobiotics in vivo. In this concise review, mechanisms by which AhR trans-activates downstream target gene expression, modulates immune responses, and mediates malignant transformation and tumor development are discussed. Moreover, activation of AhR by post-translational modifications and crosstalk with other transcription factors or signaling pathways are also summarized.

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