scholarly journals The positive feedback loop of NHE1-ERK phosphorylation mediated by BRAFV600E mutation contributes to tumorigenesis and development of glioblastoma

2021 ◽  
Author(s):  
Yuhui Li ◽  
Dan Li ◽  
Yankun Liu ◽  
Shuqing Wang ◽  
Mingyang Sun ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Brafv600e Mutation ◽  
Positive Feedback Loop ◽  
Erk Phosphorylation

scholarly journals Positive feedback loop of regulating ERK phosphorylation in mESCs mediated by Etv5-Tet2-Fgfr2 axis

2019 ◽  
Author(s):  
Chen Fan ◽  
Kui Zhu ◽  
Yuan Liu ◽  
Mengyao Zhang ◽  
Hongxia Cao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Dynamic Equilibrium ◽  
Embryonic Stem ◽  
Feedback Loops ◽  
Fibroblast Growth ◽  
Positive Feedback Loop ◽  
Erk Phosphorylation

ABSTRACTDynamic equilibrium of extracellular signal-regulated kinase (ERK) activity is regulated elaborately by multiple feedback loops to ensure the normal self-renewal of mouse embryonic stem cells (mESCs). Previous studies on mESCs have demonstrated that the negative feedback loops are engaged to prevent the overactivated ERK phosphorylation (pERK). It is not clear whether there is any positive feedback loop involved to maintain a minimum of pERK in mESCs. Here, we found that blocking fibroblast growth factor (FGF)-ERK pathway by chemical PD0325901 downregulated the transcription of E26 transformation-specific (ETS) family transcription factor Etv5 in mESCs. In turn, knockout (KO) of Etv5 by CRISPR/Cas9 decreased pERK. Moreover, Etv5 KO enhanced the DNA methylation at promoter of fibroblast growth factor receptor 2 (Fgfr2) by downregulating DNA hydroxylase Tet2, which further decreased the expression of Fgfr2 in mESCs. Collectively, a positive feedback loop of regulating pERK was revealed in mESCs, which was mediated by Etv5-Tet2-Fgfr2 axis. Our findings provide a new paradigm for pERK regulation in mESCs and will be useful to understand the cell fate determination during early embryo development.

scholarly journals The Positive Feedback Loop of NHE1-ERK Phosphorylation Mediated by BRAFV600E Mutation Contributes to Tumorigenesis and Development of Glioblastoma

2021 ◽  
Author(s):  
Yuhui Li ◽  
Dan Li ◽  
Yankun Liu ◽  
Shuqing Wang ◽  
Mingyang Sun ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Inhibitory Effect ◽  
Occurrence Rate ◽  
Positive Feedback Loop ◽  
Downstream Target ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
Activating Mutation ◽  
Proliferation And Invasion

Abstract The occurrence rate of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) activating mutation V600E (BRAFV600E) in glioblastoma multiforme (GBM) is more than 50%. Na/H exchanger 1 (NHE1), a main pH regulator affecting cell microenvironment, is hyper-expressed in GBM. However, the relationship between BRAFV600E signal pathway and NHE1 in GMB cells remains unclear. This study found that NHE1 was a downstream target of BRAFV600E and an upstream factor of extracellular signal-regulated kinase (ERK). In addition, there was a positive feedback loop between NHE1-ERK phosphorylation under regulation of BRAFV600E mutation contributing to the proliferation and invasion of GBM cells. Moreover, the proliferation and invasion abilities of BRAFV600E-mutant and BRAF wild type GBM cells were all suppressed by the NHE1 inhibitor, BRAFV600E inhibitor and combination of them. The inhibitory effect of combination of the two inhibitors was better than each single drug both in vitro and in vivo. Combination of BRAFV600E and NHE1 inhibitors could be considered as a new therapeutic regimen for GBM, especially for GBM with BRAFV600E.

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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