Inhibition of Ribosome Biogenesis In Vivo Causes p53-Dependent Death and p53-Independent Dysfunction
Language
English
Publication Date
1-1-2025
Journal
Cellular and Molecular Gastroenterology and Hepatology
DOI
10.1016/j.jcmgh.2025.101496
PMID
40081569
PMCID
PMC12198032
PubMedCentral® Posted Date
3-11-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Background & aims: Although it is well-known that ribosomes are critical for cell function, and their synthesis (known as ribosome biogenesis [RiBi]) is energy-intensive, surprisingly little is known about RiBi in vivo in adult tissue.
Methods: Using a mouse model with conditional deletion of Nat10, an essential gene for RiBi and subsequent translation of mRNA, we investigated the effects of RiBi blockade in vivo, with a focus on pancreatic acinar cells during homeostasis and tumorigenesis.
Results: We observed an unexpected latency of several weeks between Nat10 deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death. Although deletion of Trp53 rescued acinar cells from apoptotic cell death, Nat10Δ/Δ; Trp53Δ/Δ acinar cells remained morphologically and functionally abnormal. Deletion of Nat10 in acinar cells blocked Kras-oncogene-driven pancreatic ductal adenocarcinoma, regardless of Trp53 mutation status.
Conclusions: Together, our results provide initial insights into how differentiated cells respond to defects in RiBi and translation in vivo in various physiological contexts.
Keywords
Animals, Tumor Suppressor Protein p53, Ribosomes, Mice, Pancreatic Neoplasms, Acinar Cells, Apoptosis, Carcinoma, Pancreatic Ductal, Proto-Oncogene Proteins p21(ras), Mice, Knockout, Organelle Biogenesis, N-Acetyltransferase 10, Nucleolus, Paligenosis, Ribosome, p53
Published Open-Access
yes
Recommended Citation
Cho, Charles J; Nguyen, Thanh; Rougeau, Amala K; et al., "Inhibition of Ribosome Biogenesis In Vivo Causes p53-Dependent Death and p53-Independent Dysfunction" (2025). Faculty and Staff Publications. 4978.
https://digitalcommons.library.tmc.edu/baylor_docs/4978
Included in
Health Services Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Specialties Commons, Microbiology Commons