PLoS genetics, 2024-05, Vol.20 (5), p.e1011290
2024
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- Autor(en) / Beteiligte
- Titel
- miR-34a is a tumor suppressor in zebrafish and its expression levels impact metabolism, hematopoiesis and DNA damage
- Ist Teil von
- PLoS genetics, 2024-05, Vol.20 (5), p.e1011290
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2024
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Li-Fraumeni syndrome is caused by inherited TP53 tumor suppressor gene mutations. MicroRNA miR-34a is a p53 target and modifier gene. Interestingly, miR-34 triple-null mice exhibit normal p53 responses and no overt cancer development, but the lack of miR-34 promotes tumorigenesis in cancer-susceptible backgrounds. miR-34 genes are highly conserved and syntenic between zebrafish and humans. Zebrafish miR-34a and miR-34b/c have similar expression timing in development, but miR-34a is more abundant. DNA damage by camptothecin led to p53-dependent induction of miR-34 genes, while miR-34a mutants were adult-viable and had normal DNA damage-induced apoptosis. Nevertheless, miR-34a-/- compound mutants with a gain-of-function tp53R217H/ R217H or tp53-/- mutants were more cancer-prone than tp53 mutants alone, confirming the tumor-suppressive function of miR-34a. Through transcriptomic comparisons at 28 hours post-fertilization (hpf), we characterized DNA damage-induced transcription, and at 8, 28 and 72 hpf we determined potential miR-34a-regulated genes. At 72 hpf, loss of miR-34a enhanced erythrocyte levels and up-regulated myb-positive hematopoietic stem cells. Overexpression of miR-34a suppressed its reporter mRNA, but not p53 target induction, and sensitized injected embryos to camptothecin but not to γ-irradiation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7404, 1553-7390eISSN: 1553-7404DOI: 10.1371/journal.pgen.1011290Titel-ID: cdi_proquest_miscellaneous_3061781391
- Format
- –
- Schlagworte
- Analysis, Animals, Apoptosis, Apoptosis - genetics, Biology and Life Sciences, Camptothecin, Camptothecin - pharmacology, Cancer, Cell cycle, Colorectal cancer, Cyclin-dependent kinases, Danio rerio, Development and progression, DNA, DNA Damage, Embryos, Ethylenediaminetetraacetic acid, Fertilization, Gene expression, Gene Expression Regulation, Developmental, Gene mutations, Genes, Tumor Suppressor, Genetic aspects, Genetic transcription, Hematopoiesis, Hematopoiesis - genetics, Hematopoietic stem cells, Hemopoiesis, Humans, Kinases, Li-Fraumeni syndrome, Li-Fraumeni Syndrome - genetics, Medical prognosis, Medicine and Health Sciences, Messenger RNA, Metabolism, Mice, MicroRNA, MicroRNAs, MicroRNAs - genetics, MicroRNAs - metabolism, miRNA, Mutants, Mutation, Ontology, p53 Protein, Research and Analysis Methods, RNA polymerase, Scientific equipment and supplies industry, Senescence, Synteny, Transcription factors, Transcriptomics, Tumor proteins, Tumor suppressor genes, Tumor Suppressor Protein p53 - genetics, Tumor Suppressor Protein p53 - metabolism, Tumorigenesis, Tumors, Zebra fish, Zebrafish, Zebrafish - genetics, Zebrafish Proteins - genetics, Zebrafish Proteins - metabolism, γ Radiation