Similar Datasets
Project description:Background and aims: P53 limits the self-renewal of stem cells from various tissue. A Loss of p53 in combination with other oncogenic events results in aberrant self-renewal and transformation of progenitor cells. Here, we investigated whether a loss of p53 as a single genetic lesion is sufficient to induce liver tumor formation. Methods: AlfpCre mice were crossed with Trp53 conditional knockout mice to achieve a liver-specific loss of Trp53. Results: The liver-specific loss of Trp53 results in liver tumor formation. A high percentage of the tumors showed a mixed differentiation of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Conclusion: The liver-specific deletion of Trp53 is sufficient to induce liver tumor formation.
2021-01-22 | GSE156253 | GEO
Project description:Background and aims: P53 limits the self-renewal of stem cells from various tissue. A Loss of p53 in combination with other oncogenic events results in aberrant self-renewal and transformation of progenitor cells. Here, we investigated whether a loss of p53 as a single genetic lesion is sufficient to induce liver tumor formation. Methods: AlfpCre mice were crossed with Trp53 conditional knockout mice to achieve a liver-specific loss of Trp53. Results: The liver-specific loss of Trp53 results in liver tumor formation. A high percentage of the tumors showed a mixed differentiation of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Conclusion: The liver-specific deletion of Trp53 is sufficient to induce liver tumor formation.
2021-01-22 | GSE156252 | GEO
Project description:aCGH analysis of liver tumors generated in C57BL/6J mice with a liver specific loss of Trp53-/-
| PRJNA657237 | ENA
Project description:aCGH analysis of liver tumors generated in C57BL/6J mice with a liver specific loss of Trp53-/- [Agilent-027411]
| PRJNA657191 | ENA
Project description:aCGH analysis of liver tumors generated in C57BL/6J mice with a liver specific loss of Trp53-/- [Agilent-024427]
| PRJNA657193 | ENA
Project description:Background and aims: A coordinated stress and regenerative response is important following hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the CHK2/ p53/ p21 pathway in a murine model of metabolic liver injury. Methods: NTBC was reduced or withdrawn in Fah / mice lacking Chk2, p53 or p21, and survival, tumor development, liver injury and regeneration were analyzed. Partial hepatectomies were performed and mice were challenged with the Fas-antibody Jo2. Results: In a model of metabolic liver injury, loss of p53, but not of Chk2, impairs the oxidative stress re-sponse and aggravates liver damage, indicative of a direct p53-dependent protective effect on hepatocytes. Cell cycle control during chronic liver injury critically depends on the presence of both p53 and its downstream effector p21. In p53-deficient hepatocytes, unchecked proliferation occurs despite a strong induction of p21, revealing a complex interdependency between p21 and p53. The increased regenerative potential in the absence of p53 cannot fully compensate the surplus injury and is not sufficient to promote survival. Despite the different phenotypes as-sociated with the loss of individual components of the DNA damage response, gene expression patterns are dominated by the severity of liver injury, but reflect distinct effects of p53 on prolif-eration and the anti-oxidative stress response. Conclusion: Characteristic phenotypes result from the genetic abrogation of individual components of the DNA damage response cascade in a liver injury model. The extent to which loss of gene function can be compensated, or affects injury and proliferation, depends on the level at which the cas-cade is interrupted.
2021-04-02 | GSE156251 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-04-02 | GSE156983 | GEO
Project description:Hypoxia-inducible factor 1-? (HIF-1?) plays a critical role in angiogenesis-osteogenesis coupling during bone development and bone regeneration. Previous studies have shown that 17?-estradiol activates the HIF-1? signaling pathway and that mice with conditional activation of the HIF-1? signaling pathway in osteoblasts are protected from ovariectomy (OVX)-induced bone loss. In addition, it has been shown that hypoxia facilitates the osteogenic differentiation of mesenchymal stem cells (MSCs) and modulates Wnt/?-catenin signaling. Therefore, we hypothesized that activation of the HIF-1? signaling pathway by hypoxia-mimicking agents would prevent bone loss due to estrogen deficiency. In this study, we confirmed the effect of dimethyloxalylglycine (DMOG), a hypoxia-mimicking agent, on the HIF-1? signaling pathway and investigated the effect of DMOG on MSC osteogenic differentiation and the Wnt/?-catenin signaling pathway. We then investigated the effect of DMOG treatment on OVX-induced bone loss. Female C57BL/6J mice were divided into sham, OVX, OVX+L-DMOG (5 mg/kg/day), and OVX+H-DMOG (20 mg/kg/day) groups. At sacrifice, static and dynamic bone histomorphometry were performed with micro computed tomography (micro-CT) and undecalcified sections, respectively. Bone strength was assessed with the three-point bending test, and femur vessels were reconstructed and analyzed by micro-CT. Serum vascular endothelial growth factor (VEGF), osteocalcin, and C-terminal telopeptides of collagen type(CTX) were measured by ELISA. Tartrate-resistant acid phosphatase staining was used to assess osteoclast formation. Alterations in the HIF-1? and Wnt/?-catenin signaling pathways in the bone were detected by western blot. Our results showed that DMOG activated the HIF-1? signaling pathway, which further activated the Wnt/?-catenin signaling pathway and enhanced MSC osteogenic differentiation. The micro-CT results showed that DMOG treatment improved trabecular bone density and restored the bone microarchitecture and blood vessels in OVX mice. Bone strength was also partly restored in DMOG-treated OVX mice. Dynamic bone histomorphometric analysis of the femur metaphysic revealed that DMOG increased the mineralizing surface, mineral apposition rate, and bone formation rate. The serum levels of VEGF and osteocalcin were higher in DMOG-treated OVX mice. However, there were no significant differences in serum CTX or in the number of tartrate-resistant acid phosphatase-stained cells between DMOG-treated OVX mice and OVX mice. Western blot results showed that DMOG administration partly rescued the decrease in HIF-1? and ?-catenin expression following ovariectomy. Collectively, these results indicate that DMOG prevents bone loss due to ovariectomy in C57BL/6J mice by enhancing angiogenesis and osteogenesis, which are associated with activated HIF-1? and Wnt/?-catenin signaling pathways.
| S-EPMC4231053 | biostudies-literature
Project description:aCGH analysis of liver tumors generated in FAH-/- Trp53-/- mice, a mouse model of metabolic liver injury
| PRJNA657190 | ENA
Project description:BALB/c mice heterozygous for Trp53 develop a high proportion of spontaneous mammary tumors, a phenotype distinct from other mouse strains. BALB/c-Trp53+/- female mice, thus, resemble the hereditary Li-Fraumeni syndrome (LFS) characterized by early-onset of breast cancer, even though LFS involves TP53 mutations, which may involve not only loss- but also gain-of-function. Previous analysis of tumors in BALB/c-Trp53+/- females showed frequent loss of heterozygosity involving the wild-type allele of Trp53 and displayed characteristics indicative of mitotic recombination. Critical involvement of DNA double-strand break (DSB) repair dysfunction, particularly of homologous recombination (HR), was also noticed in the etiology of human breast cancer. To better define functional alterations in BALB/c-Trp53+/- mice, we applied a fluorescence-based DSB repair assay on mouse embryonic fibroblasts (MEFs) from BALB/c-Trp53+/- versus C57BL/6J-Trp53+/- mice. This approach revealed deregulation of HR but not non-homologous end-joining (NHEJ) in BALB/c-Trp53+/-, which was further confirmed for mammary epithelial cells. Screening of a small interfering RNA-library targeting DSB repair, recombination, replication and signaling genes, identified 25 genes causing differences between homologous DSB repair in the two strains upon silencing. Interactome analysis of the hits revealed clustering of replication-related and fanconi anemia (FA)/breast cancer susceptibility (BRCA) genes. Further dissection of the functional change in BALB/c-Trp53+/- by immunofluorescence microscopy of nuclear 53BP1, Replication protein A (RPA) and Rad51 foci uncovered differences in crosslink and replication-associated repair. Chromosome breakage, G2 arrest and biochemical analyses indicated a FA pathway defect downstream of FancD2 associated with reduced levels of BRCA2. Consistent with polygenic models for BRCA, mammary carcinogenesis in BALB/c-Trp53+/- mice may, therefore, be promoted by a BRCA modifier allele in the FA pathway in the context of partial p53 loss-of-function.
| S-EPMC3898496 | biostudies-literature