scholarly journals 3-Methylcholanthrene Induces Chylous Ascites in TCDD-Inducible Poly-ADP-Ribose Polymerase (Tiparp) Knockout Mice

2019 ◽  
Vol 20 (9) ◽  
pp. 2312 ◽  
Author(s):  
Tiffany E. Cho ◽  
Debbie Bott ◽  
Shaimaa Ahmed ◽  
David Hutin ◽  
Alvin Gomez ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Target Gene ◽  
Liver Toxicity ◽  
Day Treatment ◽  
Chylous Ascites ◽  
Toxicological Effects ◽  
Aryl Hydrocarbon ◽  
Wasting Syndrome ◽  
Abdominal Organs ◽  
Increased Sensitivity

TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp−/− mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp−/− mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp−/− or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP’s role as a repressor of AHR signaling, 3MC-treated Tiparp−/− mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp−/− mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp−/− mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp−/− mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp−/− mice. Our study reveals that Tiparp−/− mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome.

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.

scholarly journals Hsa-miR-105-1 Regulates Cisplatin-Resistance in Ovarian Carcinoma Cells by Targeting ANXA9

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Xinxin Kou ◽  
Hui Ding ◽  
Lei Li ◽  
Hongtu Chao
Keyword(s):  
Ovarian Carcinoma ◽  
Cell Lines ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Qrt Pcr ◽  
Gene Assay ◽  
Increased Sensitivity

Purpose. Cisplatin is one of the most effective drugs for treating ovarian carcinoma (OC), which is among the most lethal types of carcinoma. However, the chemoresistance to cisplatin that develops over time leads to a poor clinical outcome for many OC patients. Therefore, it is necessary to clearly understand the molecular mechanisms of chemoresistance. In this study, we examined how Hsa-miR-105-1 functions in cisplatin-resistant OC cells. Methods. The levels of Hsa-miR-105-1 expression in cisplatin-sensitive and resistant OC cell lines were detected by qRT-PCR. The target gene of Hsa-miR-105-1 was predicted by using the TargetScan and Starbase databases and verified by the double luciferase reporter gene assay. The target gene of Hsa-miR-105-1 was identified as ANXA9, and ANXA9 expression was evaluated by qRT-PCR, western blotting, and immunofluorescence. To validate the function of Hsa-miR-105-1 in OC cells, we silenced or overexpressed Hsa-miR-105-1 in cisplatin-sensitive or resistant OC cell lines, respectively. Furthermore, the expression levels of several apoptosis-related proteins, including P53, P21, E2F1, Bcl-2, Bax, and caspase-3, were examined by western blot analysis. Results. The levels of Hsa-miR-105-1 expression were abnormally downregulated in cisplatin-resistant OC cells, while ANXA9 expression was significantly upregulated in those cells. Treatment with an Hsa-miR-105-1 inhibitor promoted the expression of ANXA9 mRNA and protein, enhanced the resistance to cisplatin, and attenuated the cell apoptosis induced by cisplatin in cisplatin-sensitive OC cells. Moreover, treatment with Hsa-miR-105-1 mimics inhibited ANXA9 expression, which further increased the levels of P53, P21, and Bax expression and decreased the levels of E2F1 and Bcl-2 expression, finally resulting in an increased sensitivity to cisplatin in cisplatin-resistant OC cells. Conclusion. We found that a downregulation of Hsa-miR-105-1 expression enhanced cisplatin-resistance, while an upregulation of Hsa-miR-105-1 restored the sensitivity of OC cells to cisplatin. The Hsa-miR-105-1/ANXA9 axis plays an important role in the cisplatin-resistance of OC cells.

scholarly journals Dietary AhR Ligands Regulate AhRR Expression in Intestinal Immune Cells and Intestinal Microbiota Composition

2020 ◽  
Vol 21 (9) ◽  
pp. 3189 ◽  
Author(s):  
Oliver Schanz ◽  
Rieka Chijiiwa ◽  
Sevgi Can Cengiz ◽  
Yasmin Majlesain ◽  
Heike Weighardt ◽  
...  
Keyword(s):  
Intestinal Microbiota ◽  
Immune Cells ◽  
High Fat Diet ◽  
Target Gene ◽  
Microbiota Composition ◽  
Wild Type ◽  
Aryl Hydrocarbon ◽  
Reporter Mice ◽  
Induced Changes ◽  
Deficient Mice

A diet rich in vegetables and fruit is generally considered healthy because of a high content of phytochemicals, vitamins, and fiber. The phytochemical indole-3-carbinol (I3C), a derivative of glucobrassicin, is sold as a dietary supplement promising diverse health benefits. I3C metabolites act as ligands of the aryl hydrocarbon receptor (AhR), an important sensor for environmental polyaromatic chemicals. Here, we investigated how dietary AhR ligand supplementation influences AhR target gene expression and intestinal microbiota composition. For this, we used AhR repressor (AhRR)-reporter mice as a tool to study AhR activation in the intestine following dietary I3C-supplementation in comparison with AhR ligand-deprived diets, including a high fat diet. AhRR expression in intestinal immune cells was mainly driven by dietary AhR ligands and was independent of microbial metabolites. A lack of dietary AhR ligands caused enhanced susceptibility to dextran sodium sulfate (DSS)-induced colitis and correlated with the expansion of Enterobacteriaceae, whereas Clostridiales, Muribaculaceae, and Rikenellaceae were strongly reduced. I3C supplementation largely reverted this effect. Comparison of I3C-induced changes in microbiota composition using wild-type (WT), AhRR-deficient, and AhR-deficient mice revealed both AhR-dependent and -independent alterations in the microbiome. Overall, our study demonstrates that dietary AhR ligand supplementation has a profound influence on Ahrr expression in intestinal immune cells as well as microbiota composition.

scholarly journals Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass

2015 ◽  
Vol 112 (51) ◽  
pp. 15654-15659 ◽  
Author(s):  
Corinne E. Decker ◽  
Zhengfeng Yang ◽  
Ryan Rimer ◽  
Kyung-Hyun Park-Min ◽  
Claudia Macaubas ◽  
...  
Keyword(s):  
Bone Loss ◽  
Feedback Loop ◽  
Target Gene ◽  
Transmembrane Protein ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Osteoclast Formation ◽  
Activated T Cells ◽  
Downstream Target ◽  
Skeletal Mass ◽  
Downstream Target Gene

Phospholipase C gamma-2 (PLCγ2)-dependent calcium (Ca2+) oscillations are indispensable for nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) activation and downstream gene transcription driving osteoclastogenesis during skeletal remodeling and pathological bone loss. Here we describe, to our knowledge, the first known function of transmembrane protein 178 (Tmem178), a PLCγ2 downstream target gene, as a critical modulator of the NFATc1 axis. In surprising contrast to the osteopetrotic phenotype of PLCγ2−/− mice, Tmem178−/− mice are osteopenic in basal conditions and are more susceptible to inflammatory bone loss, owing to enhanced osteoclast formation. Mechanistically, Tmem178 localizes to the ER membrane and regulates RANKL-induced Ca2+ fluxes, thus controlling NFATc1 induction. Importantly, down-regulation of Tmem178 is observed in human CD14+ monocytes exposed to plasma from systemic juvenile idiopathic arthritis patients. Similar to the mouse model, reduced Tmem178 expression in human cells correlates with excessive osteoclastogenesis. In sum, these findings identify an essential role for Tmem178 to maintain skeletal mass and limit pathological bone loss.

scholarly journals YTHDF2, a protein repressed by miR-145, regulates proliferation, apoptosis and migration in ovarian cancer cells

2020 ◽  
Author(s):  
Jie Li ◽  
Lei Wu ◽  
Meili Pei ◽  
Yun Zhang
Keyword(s):  
Ovarian Cancer ◽  
Feedback Loop ◽  
Target Gene ◽  
Epigenetic Modification ◽  
Ovarian Cancer Cells ◽  
Direct Target Gene ◽  
Direct Target ◽  
And Migration ◽  
Cancer Tissues ◽  
Proliferation And Migration

Abstract RNA methylation can reverse the methylation modification at RNA level, which is a kind of extremely important epigenetic modification. YTHDF2, as a reader of m6A modification, the function and mechanisms of in epithelial ovarian cancer(EOC) have not been elucidated so far. In this study, we demonstrated that YTHDF2 was significantly upregulated in EOC tissues compared with normal ovarian tissues, further function studies confirmed that YTHDF2 significantly promoted the proliferation and migration of EOC cell lines, and reduced the global mRNA m6A levels. Next, we found that the expression levels of miR-145 and YTHDF2 were inversely correlated in ovarian cancer tissues and cells, and YTHDF2 is the direct target gene of miR-145. Interestingly, there was a crucial crosstalk between miR-145 and YTHDF2 via a double-negative feedback loop. Overexpression of YTHDF2 rescues miR-145-induced reduction of proliferation and migration in EOC cells. To conclude, YTHDF2 and miR-145, as two crucial m6A regulators, are involved in the progression of EOC by indirectly modulating m6A levels. In view of these promising results, YTHDF2 and miR-145 may provide new insights into the carcinogenesis and new potential therapeutic targets for EOC.

scholarly journals Combination of Wnt/β-Catenin Targets S100A4 and DKK1 Improves Prognosis of Human Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 37
Author(s):  
Mathias Dahlmann ◽  
Anne Monks ◽  
Erik D. Harris ◽  
Dennis Kobelt ◽  
Marc Osterland ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Wnt Signaling ◽  
Feedback Loop ◽  
Target Gene ◽  
Patient Survival ◽  
Inverse Correlation ◽  
Free Survival ◽  
S100a4 Expression ◽  
Cancer Types ◽  
Dickkopf 1

Metastasis is directly linked to colorectal cancer (CRC) patient survival. Wnt signaling through β-catenin plays a key role. Metastasis-inducing S100A4 is a Wnt/β-catenin target gene and a prognostic biomarker for CRC and other cancer types. We aimed to identify S100A4-dependent expression alterations to better understand CRC progression and metastasis for improved patient survival. S100A4-induced transcriptome arrays, confirmatory studies in isogenic CRC cell lines with defined β-catenin genotypes, and functional metastasis studies were performed. S100A4-regulated transcriptome examination revealed the transcriptional cross-regulation of metastasis-inducing S100A4 with Wnt pathway antagonist Dickkopf-1 (DKK1). S100A4 overexpression down-regulated DKK1, S100A4 knock-down increased DKK1. Recombinant DKK1 reduced S100A4 expression and S100A4-mediated cell migration. In xenografted mice, systemic S100A4-shRNA application increased intratumoral DKK1. The inverse correlation of S100A4 and DKK1 was confirmed in five independent publicly available CRC expression datasets. Combinatorial analysis of S100A4 and DKK1 in two additional independent CRC patient cohorts improved prognosis of overall and metastasis-free survival. The newly discovered transcriptional cross-regulation of Wnt target S100A4 and Wnt antagonist DKK1 is predominated by an S100A4-induced Wnt signaling feedback loop, increasing cell motility and metastasis risk. S100A4 and DKK1 combination improves the identification of CRC patients at high risk.

scholarly journals Stimulus-selective crosstalk via the NF-κB signaling system reinforces innate immune response to alleviate gut infection

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Balaji Banoth ◽  
Budhaditya Chatterjee ◽  
Bharath Vijayaragavan ◽  
MVR Prasad ◽  
Payel Roy ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Important Determinant ◽  
Innate Immune ◽  
Signal Integration ◽  
Signaling System ◽  
Gene Expressions ◽  
Tissue Microenvironment ◽  
Β Receptor

Tissue microenvironment functions as an important determinant of the inflammatory response elicited by the resident cells. Yet, the underlying molecular mechanisms remain obscure. Our systems-level analyses identified a duration code that instructs stimulus specific crosstalk between TLR4-activated canonical NF-κB pathway and lymphotoxin-β receptor (LTβR) induced non-canonical NF-κB signaling. Indeed, LTβR costimulation synergistically enhanced the late RelA/NF-κB response to TLR4 prolonging NF-κB target gene-expressions. Concomitant LTβR signal targeted TLR4-induced newly synthesized p100, encoded by Nfkb2, for processing into p52 that not only neutralized p100 mediated inhibitions, but potently generated RelA:p52/NF-κB activity in a positive feedback loop. Finally, Nfkb2 connected lymphotoxin signal within the intestinal niche in reinforcing epithelial innate inflammatory RelA/NF-κB response to Citrobacter rodentium infection, while Nfkb2−/− mice succumbed to gut infections owing to stromal defects. In sum, our results suggest that signal integration via the pleiotropic NF-κB system enables tissue microenvironment derived cues in calibrating physiological responses.

scholarly journals Epigenetic regulation of NFE2 overexpression in myeloproliferative neoplasms

Blood ◽  
2018 ◽  
Vol 131 (18) ◽  
pp. 2065-2073 ◽  
Author(s):  
Jan C. Peeken ◽  
Jonas S. Jutzi ◽  
Julius Wehrle ◽  
Christoph Koellerer ◽  
Hans F. Staehle ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Target Gene ◽  
Myeloproliferative Neoplasms ◽  
Positive Feedback Loop ◽  
Key Points

Key Points Overexpression of NFE2 in MPNs is associated with H3Y41 phosphorylation by JAK2V617F. JMJD1C is an NFE2 target gene and acts in a positive feedback loop contributing to NFE2 overexpression in MPNs.

Sign in / Sign up

Export Citation Format

Share Document