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Tob1 is a Constitutively Expressed Repressor of Liver Regeneration

ABSTRACT: How proliferative and inhibitory cell signals integrate to control liver regeneration remains poorly understood. A screen for antiproliferative factors repressed after liver injury identified Tob1, a member of the PC3/BTG1 family of mitoinhibitory molecules as a target for further evaluation. Tob1 protein decreases after 2/3 hepatectomy in mice secondary to post-transcriptional mechanisms. Deletion of Tob1 increases hepatocyte proliferation and accelerates restoration of liver mass after hepatectomy. Down-regulation of Tob1 is required for normal liver regeneration and Tob1 controls hepatocyte proliferation in a dose-dependent fashion. Tob1 associates directly with both Caf1 and the Cyclin/cdk complex to modulate kinase activity. In addition, Tob1 has significant effects on the transcription of critical cell cycle components, including E2F targets and genes involved in p53 signaling. These studies provide direct evidence that levels of an inhibitory factor control the rate of liver regeneration. Our data identify Tob1 as a crucial check-point molecule that acts by by modulating levels and activity of cell cycle proteins.

ORGANISM(S): Mus musculus

PROVIDER: GSE21836 | GEO | 2010/05/15

SECONDARY ACCESSION(S): PRJNA126919

REPOSITORIES: GEO

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Tob1 is a Constitutively Expressed Repressor of Liver Regeneration

Project description:How proliferative and inhibitory cell signals integrate to control liver regeneration remains poorly understood. A screen for antiproliferative factors repressed after liver injury identified Tob1, a member of the PC3/BTG1 family of mitoinhibitory molecules as a target for further evaluation. Tob1 protein decreases after 2/3 hepatectomy in mice secondary to post-transcriptional mechanisms. Deletion of Tob1 increases hepatocyte proliferation and accelerates restoration of liver mass after hepatectomy. Down-regulation of Tob1 is required for normal liver regeneration and Tob1 controls hepatocyte proliferation in a dose-dependent fashion. Tob1 associates directly with both Caf1 and the Cyclin/cdk complex to modulate kinase activity. In addition, Tob1 has significant effects on the transcription of critical cell cycle components, including E2F targets and genes involved in p53 signaling. These studies provide direct evidence that levels of an inhibitory factor control the rate of liver regeneration. Our data identify Tob1 as a crucial check-point molecule that acts by by modulating levels and activity of cell cycle proteins. Samples from wild type and Tob1 null mice as normal adults and 24 hours after 2/3 hepatectomy are used. Each experimental point used data from two chips, each having a different set of three pooled animals. In summary we had 8 chips: 2 for WT time 0, 2 for WT time 24, 2 for KO time 0, 2 for KO time 24.

2010-05-28 | E-GEOD-21836 | biostudies-arrayexpress

Expression data from rat hepatocyte during liver regeneration after partial hepatectomy

2014-02-28 | GSE55434 | GEO

SHP2 inhibitor augments murine liver regeneration via cytoprotective and proproliferative pathway enhancement identified by RNA sequencing

Project description:Disruption of the liver’s innate ability to regenerate represents an “undruggable” clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional co-activator which is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent activation of YAP mediated by tyrosine-protein phosphatase non-receptor type 11 (SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. Evaluation of these effects in mice with hepatocyte-specific Yap/Taz deletion demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of non-alcoholic steatohepatitis was associated with improved survival and decreased markers of injury post-hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling. Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induce a YAP-dependent pro-proliferative and cytoprotective enhancement of liver regeneration.

2022-03-17 | GSE198641 | GEO

Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice

Project description:We studied the role of the post-translational modification called O-GlcNAcylation during liver regeneration. Here we generated O-GlcNAc transferase (OGT-KO) and O-GlcNAcase (OGA-KO) hepatocyte-specific knock-out mice. 70% partial hepatectomy (PHX) was performed to induce liver regeneration. We showed that OGA-KO mice had normal liver regeneration whereas OGT-KO mice had a defect in the termination of liver regeneration.

2022-02-25 | GSE188882 | GEO

Expression in liver tissue of wildtype (wt) or hepatocyte specific Klf6 knockout (DeltaKLF6) after partial hepatectomy

Project description:KrÃ¼ppel-like factor 6 (KLF6) is a transcription factor and tumor suppressor. Loss or reduction of KLF6 is linked with progression of experimental and human hepatocellular carcinoma. Despite its important contributions to liver homeostasis and growth, there are no data characterizing the involvement of KLF6 to hepatic regeneration. Microarray data from wildtype and DeltaKlf6 mice were used to identify regulating mechanisms and potential mediators within liver regeneration Wildtype and hepatocyte specific Klf6 knockout mice (DeltaKlf6) were employed for 70% partial liver resection/hepatectomy (PHx) in order to analyse liver regeneration. Twelve hours after partial hepatectomy animals were scrificed and remnant liver tissue was used for further experiemnts. For the overall study we used 6 animals per group, and included RNA from liver tissue of 3 wildtype and 3 DeltaKlf6 animals for the microarray analysis. Wildtype animals were used as controls.

2016-08-10 | E-GEOD-85381 | biostudies-arrayexpress

A New Liver-Regeneration Molecular Mechanism Involving Hepatic Stellate Cells, Kupffer Cells, and Glucose-Regulated Protein 78 as a New Hepatotrophic Factor

Project description:Background and aims: Lethal liver failure is an important clinical issue. To overcome liver failure, we focused on liver regeneration mechanisms by activation of HSCs and KCs. It is known that the HSC-secreted Mac-2 binding protein glycan isomer (M2BPGi) has a function to activate Kupffer cells (KCs) in fibrotic liver. However, the importance and functional mechanism of liver regeneration by HSCs/M2BPGi/KCs axis in remnant liver after hepatectomy are still unknown. The aim of this study is to clarify whether the HSCs-derived M2BPGi can activate KCs in damaged-liver by not only fibrosis but also after hepatectomy and to elucidate the new molecular mechanism of liver regeneration by HSCs and KCs. Methods: We examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi-activated KCs by proteomics approach. Further, the effect of Glucose-regulated protein 78 (GRP78) as one of the M2BPGi-related secreted proteins on liver regeneration was examined in in vitro analysis and mouse hepatectomy model. Results: Although M2BPGi had no hepatocyte promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KCs-drived GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration in 70% hepatectomy mice and increased the survival rate in lethal 90% hepatectomy mice with liver failure. Conclusion: The M2BPGi activated-KCs extract the GRP78 which facilitates liver regeneration via activation of the proliferation potency of hepatocytes. Moreover, GRP78 administration could improve the survival in the lethal mice model. Our data suggested that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure in the clinic.

2021-06-29 | GSE179005 | GEO

Effect of knockdown Tbl1xr1 on gene expression after 2/3 hepatectomy

Project description:Our spatiotemporal data confirmed activation of Tbl1xr1 in hepatocytes after 2/3 hepatectomy. TBL1XR1 is a transcriptional cofactor inducing ubiquitination and degradation of NCoR/SMRT co-repressors and NCoR is a negative regulator of hepatocyte proliferation acting through histone deacetylases (HDACs). We have examined the role of TBL1XR1 in liver regeneration through in vivo shRNA knockdown using adeno-associated viruses (shNC and shTbl1xr1) specifically targeting hepatocytes. The knockdown of Tbl1xr1 results in impair hepatocyte proliferation.To investigate the downstream targets of TBL1XR1 during liver regenration, we here perform the bulk RNA-seq for shNC and shTbl1xr1 at D2 after hepatectomy. Our data show demonstrated that Tbl1xr1 knockdown not only led to reduced cell cycle genes but also to impaired fatty acid β-oxidation as the most obviously affected liver function.

2024-02-05 | GSE254481 | GEO

RNA-seq transcriptonal profiling in partial hepatectomy liver tissues in Arid1a WT and liver specific KO mice.

Project description:Arid1a is the subunit of SWI/SNF complex, which was reported to guide SWI/SNF to DNA. Here, we found that loss of Arid1a in the liver results in improved liver regeneration after partial hepatectomy.Genome-wide analysis showed that after hepatectomy,loss of Arid1a reduces the recruitment and activity of E2F4 on target promoters, resulting in expression programs that favor regeneration during injury.RNAseq shows transcriptional profiling in WT and Arid1a LKO livers pre- and post-hepatectomy, which confirmed the E2F4 target genes and cell cycle genes were upregulated after hepatectomy. After partial hepatectomy, liver transcriptional profiling in WT and Arid1a liver specific KO mice were generated by RNA-seq analysis.

2016-03-30 | E-GEOD-76926 | biostudies-arrayexpress

Expression data from rat hepatocyte during liver regeneration after partial hepatectomy

Project description:The recovery of liver mass is mainly mediated by proliferation and enlargement of hepatocytes after partial hepatectomy. Studying the gene expression profiles of hepatocytes after partial hepatectomy will be helpful in exploring the mechanism of liver regeneration. We used microarrays to further highlight the regulatory role of hepatocyte in liver regeneration at gene transcription level. Rat liver regeneration after partial hepatectomy (PH) is a good model to study the regulation of cell proliferation. We isolated hepatocytes from regenerating liver at 9 time points (2, 6, 12,24, 30, 36, 72, 120, and 168h) after PH and measured gene expression profiles of hepatocytes from 2h to 168h with rat Genome 230 2.0 gene chip. Each sample corresponding to one time point was hybridized onto one array. The experiment was repeated 3 times for each time point. In total, 10 time points were measured and 0h was used control group. After careful quality control analyses of each chip, Affymetrix GCOS 2.0 software was used to analyze the data. The relevance of gene expression profiles and biological processes was analyzed by bioinformatics and systems biology.

2014-02-28 | E-GEOD-55434 | biostudies-arrayexpress

Survivin deficient liver of mice after partial hepatectomy

Project description:The liver possesses remarkable regenerative capacity in response to injury. Upon partial hepatectomy (PHx), terminally differentiated hepatocytes in the remaining liver enter the cell cycle and restore the liver mass and function within weeks. However, liver regeneration is often impaired in livers with chronic diseases. Survivin, an inhibitor of apoptosis protein (IAP) and member of chromosome passenger complex (CPC), plays versatile roles in cell mitosis and apoptosis. We and others found that the expression of Survivin was highly increased in liver during PHx-induced liver regeneration, which indicated that Survivin played important roles in this process. However, the function of Survivin in liver regeneration remains largely undefined. Here, using mice with genetic deletion of Survivin, we found that during PHx-induced liver regeneration Survivin regulated both hepatocyte G1/S phase transition by inhibiting the expression of p21 and G2/M phase transition by regulating the localization of CPC. Moreover, restoration of Survivin expression in Survivin-deficient hepatocytes inhibited p21 expression and promote both hepatocyte G1/S and G2/M transition during PHx-induced liver regeneration.

2017-01-01 | GSE83598 | GEO

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