title: p300 Regulates Liver Functions by Controlling p53 and C/EBP Family Proteins through Multiple Signaling Pathways.
abstract: The histone acetyltransferase p300 has been implicated in the regulation of liver biology; however, molecular mechanisms of this regulation are not known. In this paper, we examined these mechanisms using transgenic mice expressing a dominant negative p300 molecule (dnp300). While dnp300 mice did not show abnormal growth within 1 year, these mice have many alterations in liver biology and liver functions. We found that the inhibition of p300 leads to the accumulation of heterochromatin foci in the liver of 2-month-old mice. Transcriptome sequencing (RNA-Seq) analysis showed that this inhibition of p300 also causes alterations of gene expression in many signaling pathways, including chromatin remodeling, apoptosis, DNA damage, translation, and activation of the cell cycle. Livers of dnp300 mice have a high rate of proliferation and a much higher rate of proliferation after partial hepatectomy. We found that livers of dnp300 mice are resistant to CCl4-mediated injury and have reduced apoptosis but have increased proliferation after injury. Underlying mechanisms of resistance to liver injury and increased proliferation in dnp300 mice include ubiquitin-proteasome-mediated degradation of C/EBPα and translational repression of the p53 protein by the CUGBP1-eukaryotic initiation factor 2 (eIF2) repressor complex. Our data demonstrate that p300 regulates a number of critical signaling pathways that control liver functions.
authors.affiliation: Department of Pathology and Immunology and Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Breaux
authors.affiliation: Department of Pathology and Immunology and Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Lewis
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Valanejad
authors.affiliation: Department of Pathology and Immunology and Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Polina
authors.initials: P
authors.lastname: Iakova
authors.affiliation: Department of Pathology and Immunology and Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Fengju
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Pathology and Immunology and Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Department of Pathology and Immunology and Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Estela
authors.initials: E
authors.lastname: Medrano
authors.affiliation: Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Lubov
authors.initials: L
authors.lastname: Timchenko
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA Nikolai.Timchenko@cchmc.org.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Timchenko
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D000067879:CELF1 Protein; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D050881:E1A-Associated p300 Protein / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics / Q000517:prevention & control; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000601:surgery; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D000067879:CELF1 Protein; C502743:CELF1 protein, mouse; D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; D006570:Heterochromatin; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse