EGF Activates Autocrine TGFα to Induce Prolonged EGF Receptor Signaling and Hepatocyte Proliferation

Liu, ShuZheng; Wierød, Lene; Skarpen, Ellen; Grøsvik, H.; Duan, Guangcai; Huitfeldt, Henrik S.

doi:10.1159/000354454

Cited by 10 publications

(6 citation statements)

References 33 publications

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“…It has been reported that specific TFs, such as, C/EBP, AP-1, STAT3, EGF and NF-κB are rapidly activated in the remnant liver tissues shortly after PH [10,11,[18][19][20][21][22][23]. These events were followed by the first phase of gene expression alteration, including the upregulation of a group of promitogenic proto-oncogenes (e.g.…”

Section: Discussionmentioning

confidence: 99%

An Integrated Approach for the Identification of HNF4α-Centered Transcriptional Regulatory Networks During Early Liver Regeneration

Jiao

Zhu

et al. 2015

Cell Physiol Biochem

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Background/Aims: Hepatocyte nuclear factor-4α (HNF4α), the liver enriched transcription factor (TF), is one of the major regulators of hepatocyte differentiation and proliferation. However, how HNF4α participate in liver regeneration after partial hepatectomy (PH) remains largely unknown. In order to identify the HNF4α-centered regulatory network, we applied an integrated analytic strategy, in which, TF array, mRNA microarray, bioinformatic analysis and ChIP-on-chip assays were integrated. Methods/Results: The TF signatures from MOUSE OATFA (TF-array) platform revealed that the activity of HNF4α was significantly reduced and 17 other TFs showed increased activity at 4 h post PH. Then the ChIP-on-chip analysis on HNF4α were combined with mRNA expression profiling to select the possible HNF4α target genes during early liver regeneration, which were then sub-grouped according to their signaling pathways. More specifically, the HNF4α target genes with the gene ontology (GO) terms of cytokine-cytokine receptor, Jak-STAT, MAPK, toll-like receptor and insulin signaling pathways were further analyzed with an advanced bioinformatics tool named oPOSSUM to identify TF binding sites occupancy and predict the co-regulatory relationship between TFs and targets. Furthermore, we identified that repressed HNF4α during the early phase of liver regeneration may contribute cooperatively to the induction of immediate early genes, such as, c-fos, c-jun and stat3. Conclusion: our data indicate that HNF4α may play an inhibitory role on the induction of specific promitogenic genes and liver regeneration initiation. The integrated approach of mRNA/OATFA/ChIP-DSL/oPOSSUM analysis may help us better characterize the target genes and co-regulatory network of HNF4α during the early stage of liver regeneration.

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Section: Discussionmentioning

confidence: 99%

An Integrated Approach for the Identification of HNF4α-Centered Transcriptional Regulatory Networks During Early Liver Regeneration

Jiao

Zhu

et al. 2015

Cell Physiol Biochem

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“…Activating Gp1 mGluRs leads to elevated Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) or Extracellular Signal-regulated Kinase-1/2 (ERK1/2) signaling (14)(15)(16), which in turn activates eIF4E and translation initiation (17)(18)(19)(20)(21). Several recent studies have also demonstrated that translation elongation is facilitated upon mGluR activation through the phosphorylation of eukaryotic elongation factor 2 (eEF2) (22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Mdm2 mediates FMRP- and Gp1 mGluR-dependent protein translation and neural network activity

Liu

Seimetz

Lee

et al. 2017

Human Molecular Genetics

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Activating Group 1 (Gp1) metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, elicits translation-dependent neural plasticity mechanisms that are crucial to animal behavior and circuit development. Dysregulated Gp1 mGluR signaling has been observed in numerous neurological and psychiatric disorders. However, the molecular pathways underlying Gp1 mGluR-dependent plasticity mechanisms are complex and have been elusive. In this study, we identified a novel mechanism through which Gp1 mGluR mediates protein translation and neural plasticity. Using a multi-electrode array (MEA) recording system, we showed that activating Gp1 mGluR elevates neural network activity, as demonstrated by increased spontaneous spike frequency and burst activity. Importantly, we validated that elevating neural network activity requires protein translation and is dependent on fragile X mental retardation protein (FMRP), the protein that is deficient in the most common inherited form of mental retardation and autism, fragile X syndrome (FXS). In an effort to determine the mechanism by which FMRP mediates protein translation and neural network activity, we demonstrated that a ubiquitin E3 ligase, murine double minute-2 (Mdm2), is required for Gp1 mGluR-induced translation and neural network activity. Our data showed that Mdm2 acts as a translation suppressor, and FMRP is required for its ubiquitination and down-regulation upon Gp1 mGluR activation. These data revealed a novel mechanism by which Gp1 mGluR and FMRP mediate protein translation and neural network activity, potentially through de-repressing Mdm2. Our results also introduce an alternative way for understanding altered protein translation and brain circuit excitability associated with Gp1 mGluR in neurological diseases such as FXS.

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“…18 Park7 has been shown to facilitate liver progenitor cell expansion in a 3,5diethoxycarbonyl-1,4-dihydrocollidine diet-induced liver injury murine model 19 and promote the development of diethylnitrosamine-induced hepatocellular carcinoma 20 ; Park7 deficiency could improve carbon tetrachlorideinduced liver fibrosis and liver ischemia-reperfusion injury. 18,21 Several previous studies have shown that Park7 could activate several signalling pathways, such as ERK1/2 and PI3K/Akt, which are well documented to play a pro-proliferation role in liver regeneration 22,23 ; however, the role of Park7 in liver regeneration has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

PARK7 deficiency inhibits fatty acid β‐oxidation via PTEN to delay liver regeneration after hepatectomy

Wen

Jiao

et al. 2022

Clinical & Translational Med

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Background & aims Transient regeneration–associated steatosis (TRAS) is a process of temporary hepatic lipid accumulation and is essential for liver regeneration by providing energy generated from fatty acid β‐oxidation, but the regulatory mechanism underlying TRAS remains unknown. Parkinsonism‐associated deglycase (Park7)/Dj1 is an important regulator involved in various liver diseases. In nonalcoholic fatty liver diseased mice, induced by a high‐fat diet, Park7 deficiency improves hepatic steatosis, but its role in liver regeneration remains unknown Methods Park7 knockout (Park7−/−), hepatocyte‐specific Park7 knockout (Park7△hep) and hepatocyte‐specific Park7‐Pten double knockout mice were subjected to 2/3 partial hepatectomy (PHx) Results Increased PARK7 expression was observed in the regenerating liver of mice at 36 and 48 h after PHx. Park7−/− and Park7△hep mice showed delayed liver regeneration and enhanced TRAS after PHx. PPARa, a key regulator of β‐oxidation, and carnitine palmitoyltransferase 1a (CPT1a), a rate‐limiting enzyme of β‐oxidation, had substantially decreased expression in the regenerating liver of Park7△hep mice. Increased phosphatase and tensin homolog (PTEN) expression was observed in the liver of Park7△hep mice, which might contribute to delayed liver regeneration in these mice because genomic depletion or pharmacological inhibition of PTEN restored the delayed liver regeneration by reversing the downregulation of PPARa and CPT1a and in turn accelerating the utilization of TRAS in the regenerating liver of Park7△hep mice Conclusion Park7/Dj1 is a novel regulator of PTEN‐dependent fatty acid β‐oxidation, and increasing Park7 expression might be a promising strategy to promote liver regeneration.

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EGF Activates Autocrine TGFα to Induce Prolonged EGF Receptor Signaling and Hepatocyte Proliferation

Cited by 10 publications

References 33 publications

An Integrated Approach for the Identification of HNF4α-Centered Transcriptional Regulatory Networks During Early Liver Regeneration

An Integrated Approach for the Identification of HNF4α-Centered Transcriptional Regulatory Networks During Early Liver Regeneration

Mdm2 mediates FMRP- and Gp1 mGluR-dependent protein translation and neural network activity

PARK7 deficiency inhibits fatty acid β‐oxidation via PTEN to delay liver regeneration after hepatectomy

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