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1.
Cell Death Dis ; 7(6): e2250, 2016 06 02.
Article in English | MEDLINE | ID: mdl-27253414

ABSTRACT

An important regulator of inflammatory signalling is the ubiquitin-editing protein A20 that acts as a break on nuclear factor-κB (NF-κB) activation, but also exerts important cytoprotective functions. A20 knockout mice are cachectic and die prematurely due to excessive multi-organ inflammation. To establish the importance of A20 in liver homeostasis and pathology, we developed a novel mouse line lacking A20 specifically in liver parenchymal cells. These mice spontaneously develop chronic liver inflammation but no fibrosis or hepatocellular carcinomas, illustrating an important role for A20 in normal liver tissue homeostasis. Hepatocyte-specific A20 knockout mice show sustained NF-κB-dependent gene expression in the liver upon tumor necrosis factor (TNF) or lipopolysaccharide injection, as well as hepatocyte apoptosis and lethality upon challenge with sublethal doses of TNF, demonstrating an essential role for A20 in the protection of mice against acute liver failure. Finally, chronic liver inflammation and enhanced hepatocyte apoptosis in hepatocyte-specific A20 knockout mice was associated with increased susceptibility to chemically or high fat-diet-induced hepatocellular carcinoma development. Together, these studies establish A20 as a crucial hepatoprotective factor.


Subject(s)
Apoptosis , Cytoprotection , Hepatocytes/metabolism , Hepatocytes/pathology , Inflammation/pathology , Liver Neoplasms/pathology , Liver/pathology , Tumor Necrosis Factor alpha-Induced Protein 3/metabolism , Animals , Apoptosis/drug effects , Carcinogenesis/drug effects , Carcinogenesis/metabolism , Carcinogenesis/pathology , Chronic Disease , Cytokines/metabolism , Cytoprotection/drug effects , Diet, High-Fat , Fas-Associated Death Domain Protein/metabolism , Gene Deletion , Hepatitis/metabolism , Hepatitis/pathology , Hepatocytes/drug effects , Inflammation/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Liver/drug effects , Liver Neoplasms/metabolism , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/metabolism , Phenotype , Tumor Necrosis Factor alpha-Induced Protein 3/deficiency , Tumor Necrosis Factor-alpha/pharmacology
2.
Vet Pathol ; 52(4): 752-6, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25253064

ABSTRACT

Nongestational ovarian choriocarcinoma (NGCO) is a tumor of germ cell origin seldom described in nonhuman species. Few spontaneous cases are reported in macaques and mice, with the B6C3F1 strain overrepresented. This report describes 2 cases of ovarian choriocarcinoma in nulliparous female mice with conditional loss of Trp53 under the Tie2 promoter. The mouse line was maintained on a mixed genetic background including Crl: CD1(ICR) and 129X1/SvJ strains. In both cases, affected ovary was partially replaced by blood-filled lacunae lined by neoplastic trophoblast-like giant cells. Immunohistochemically, neoplastic cells expressed folate-binding protein and prolactin and were invariably negative for p53. To the authors' knowledge, this is the first report characterizing this entity in a genetically engineered mouse (GEM) line. Considering that germ cells (the cell population from which NGCO originates) constitutively express Tie2 receptor, it can be speculated that Tie2-driven deletion of Trp53 may have played a role in the development of these tumors.


Subject(s)
Choriocarcinoma/veterinary , Neoplasms, Germ Cell and Embryonal/veterinary , Ovarian Neoplasms/veterinary , Receptor, TIE-2/genetics , Tumor Suppressor Protein p53/genetics , Animals , Choriocarcinoma/pathology , Female , Immunohistochemistry/veterinary , Mice , Mice, Inbred ICR , Mice, Transgenic , Neoplasms, Germ Cell and Embryonal/pathology , Ovarian Neoplasms/pathology , Pregnancy
3.
Cell Death Differ ; 20(7): 888-97, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23449391

ABSTRACT

There is growing evidence that the p53 tumour suppressor downregulates vascular endothelial growth factor (VEGF) expression, although the underlying mechanisms remain unclear and controversial. Here we provide insights from in vitro experiments and in vivo xenotransplantation assays that highlight a dual role for p53 in regulating VEGF during hypoxia. Unexpectedly, and for the first time, we demonstrate that p53 rapidly induces VEGF transcription upon hypoxia exposure by binding, in an HIF-1α-dependent manner, to a highly conserved and functional p53-binding site within the VEGF promoter. However, during sustained hypoxia, p53 indirectly downregulates VEGF expression via the retinoblastoma (Rb) pathway in a p21-dependent manner, which is distinct from its role in cell-cycle regulation. Our findings have important implications for cancer therapy, especially for tumours that harbour wild-type TP53 and a dysfunctional Rb pathway.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p21/metabolism , Hypoxia/metabolism , Neovascularization, Pathologic/metabolism , Retinoblastoma Protein/metabolism , Signal Transduction/physiology , Tumor Suppressor Protein p53/metabolism , Vascular Endothelial Growth Factor A/metabolism , Animals , Base Sequence , Cell Line, Tumor , Cells, Cultured , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Disease Models, Animal , Down-Regulation/physiology , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Hypoxia/physiopathology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , In Vitro Techniques , Mice , Mice, Nude , Molecular Sequence Data , Neovascularization, Pathologic/physiopathology , Transplantation, Heterologous
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