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 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 A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Siming Qu ◽  
Li Jin ◽  
Hanfei Huang ◽  
Jie Lin ◽  
Weiwu Gao ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Hbv Infection ◽  
Cell Counting ◽  
Regulation Mechanism ◽  
Dependent Manner ◽  
Liver Carcinogenesis ◽  
Nude Mouse Model ◽  
Positive Feedback Loop

Abstract Background Hepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people. Methods The expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells. Result ALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells’ growth and migration in vitro and in vivo. Conclusions HBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.

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