Hepatic p53 protein level governs liver s sensitivity to drug-induced liver injury
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA655234 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12387749.fastq.gz | Fastqsanger.gz | |||
| SRR12387750.fastq.gz | Fastqsanger.gz | |||
| SRR12387751.fastq.gz | Fastqsanger.gz | |||
| SRR12387752.fastq.gz | Fastqsanger.gz | |||
| SRR12387753.fastq.gz | Fastqsanger.gz |
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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.
2011-12-29 | GSE34760 | GEO
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.
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2023-05-04 | GSE231677 | GEO
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Project description:Lung cancer is the leading cause of cancer deaths worldwide. TP53 tumor suppressor gene mutations occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, by promoting alveolar type 1 (AT1) differentiation. Using mice expressing oncogenic Kras and null, wild-type, or hypermorphic p53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA-sequencing and ATAC-sequencing of LUAD cells uncovered a p53-induced AT1 differentiation program during tumor suppression in vivo through direct DNA binding, chromatin remodeling, and AT1 gene induction. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 differentiation in alveolar injury repair. Notably, p53 inactivation resulted in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signaling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of p53wt and p53-null mice showed that p53 also directs alveolar regeneration after injury, by regulating AT2 self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumor suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury.
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