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Epigenetic stress responses induce muscle stem cell aging by Hoxa9 developmental signals [microarray]

ABSTRACT: Background and Aims: Analysis of aging-induced impairments in satellite cells (SCs) – the stem cells of skeletal muscle that are required for its regeneration. Hox genes are known to control stem cell function and development of various tissues. Methods: We used AlfpCre mice for liver specific deletion of Trp53 in a conditional knockout mouse model to analyze liver carcinogenesis. Results: Here, we show that liver-specific deletion of p53 in mice consistently induces formation of liver carcinoma depicting bilineal differentiation. Freshly isolated p53-/- liver progenitor cells and hepatocytes exhibit chromosomal imbalances and an enhanced clonogenic capacity compared to p53-positive cells or p21-deficient cells. Primary cultures of hepatocytes and liver progenitor cells from p53-/- mice formed tumors with bilineal differentiation when transplanted into immuno-compromised mice. Together, these results indicate that loss of p53 alone is sufficient to induce primary liver cancer with bilineal differentiation originating from chromosomal instable cultured liver progenitor cells or hepatocytes. Conclusions: The study shows that p53-dependent checkpoints inhibit transformation of liver progenitor cells and hepatocytes involving p21-independent mechanisms. In this study the function of the Hoxa9 was analyzed in murine satellite cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE87811 | GEO | 2016/11/30

SECONDARY ACCESSION(S): PRJNA347652

REPOSITORIES: GEO

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p53 deletion induces liver carcinoma with bilineal differentiation

Project description:Background and Aims: p53 can limit the self-renewal of stem cells from various tissues. Experimental evidence suggests that deletion of p53 can cooperate with other oncogenic events to induce aberrant self-renewal and transformation of progenitor cells. It is not known whether p53 deletion alone can lead to liver tumor formation. Methods: We used AlfpCre mice for liver-specific deletion of Trp53 in a conditional knockout mouse model to analyze liver carcinogenesis. Results: Here, we show that liver-specific deletion of p53 in mice consistently induces formation of liver carcinoma depicting bilineal differentiation. Freshly isolated p53-/- liver progenitor cells and hepatocytes exhibit chromosomal imbalances and an enhanced clonogenic capacity compared to p53-positive cells or p21-deficient cells. Primary cultures of hepatocytes and liver progenitor cells from p53-/- mice formed tumors with bilineal differentiation when transplanted into immuno-compromised mice. Together, these results indicate that loss of p53 alone is sufficient to induce primary liver cancer with bilineal differentiation originating from chromosomal instable cultured liver progenitor cells or hepatocytes. Conclusions: The study shows that p53-dependent checkpoints inhibit transformation of liver progenitor cells and hepatocytes involving p21-independent mechanisms. Liver tumors derived from Trp53 KO mice, liver tumors from DEN-treated wildtype mice, Trp53 KO liver and wildtype liver were isolated and RNA was extracted. Agilent-026655 Mouse 4x44K v2 arrays were used.

2011-12-29 | E-GEOD-34760 | biostudies-arrayexpress

p53 deletion induces liver carcinoma with bilineal differentiation

2011-12-29 | GSE34760 | GEO

Bilineal differentiated liver carcinoma cells generates highly aggressive escape variants

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2023-05-23 | GSE215059 | GEO

aCGH analysis of liver tumors generated in C57BL/6J mice with a liver specific loss of Trp53-/- [Agilent-024427]

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aCGH analysis of liver tumors generated in C57BL/6J mice with a liver specific loss of Trp53-/- [Agilent-027411]

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aCGH analysis of liver tumors generated in FAH-/- Trp53-/- mice, a mouse model of metabolic liver injury

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.

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Disruption of the DNA damage pathway at different levels results in distinct phenotypes in a murine liver injury model

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aCGH analysis of liver tumors generated in FAH-/- mice, a mouse model of metabolic liver injury

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.

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Mus musculus

Project description:p53 deletion induces liver carcinoma with bilineal differentiation

| PRJNA150383 | ENA