التفاصيل البيبلوغرافية
| العنوان: |
Endogenous p53 Inhibitor TIRR Dissociates Systemic Metabolic Health from Oncogenic Activity |
| المؤلفون: |
Eva Tsaousidou, Jedrzej Chrzanowski, Pascal Drané, Yizhou He, Mateusz Kaminski, Dominika Michalek, Grace Y. Lee, Ekin Güney, Kalindi Parmar, Wojciech Fendler, Dipanjan Chowdhury, Gökhan S. Hotamışlıgil |
| بيانات النشر: |
Zenodo |
| سنة النشر: |
2022 |
| المجموعة: |
Zenodo |
| مصطلحات موضوعية: |
cancer, trascriptomics, python |
| الوصف: |
Many oncogenes, tumor suppressors and tumor promoting processes have been implicated in systemic metabolic regulation. However, it remains unclear if systemic metabolic health per se equals to reduced oncogenesis. Recent studies identified TIRR, an endogenous inhibitor of 53BP1‑mediated p53 activation, raising critical questions about the natural implications of preventing tumor suppressor activity in physiology. Here, we show that genetic deletion of TIRR in mice caused selective p53 activation resulting in significant protection against cancer but also in systemic metabolic imbalance. TIRR‑deficient mice were spontaneously overweight and insulin resistant. Similarly, low TIRR expression in the adipose tissue correlated with higher BMI and insulin resistance in humans. Despite the systemic metabolic impairment, TIRR loss dramatically increased survival of p53HET mice. Similarly, in humans, low TIRR expression correlated with increased progression‑free survival of patients with p53 heterozygous primary carcinomas of multiple lineages. Furthermore, systemic transcriptomic analysis of metabolically relevant mouse tissues under physiological conditions revealed a p53‑dependent TIRR signature characterized by SPINT2, which was confirmed in human carcinomas. Finally, the onco‑protective and metabolic actions of TIRR are dependent on p53 in vivo and lost upon homozygous deletion of p53 in TIRR‑deficient animals. Taken together, we describe an unexpected and contrasting role for TIRR in p53‑related oncogenesis and systemic metabolic health. ; This code has been tested on Microsoft Windows 10 (10.0.19044 Build 19044) using the Anaconda environment (version 4.8.3). The file "tirrpaper.txt" specifies the configuration of the appropriate Anaconda environment. Data required for the execution of the code (stored in relative paths ./data and ./data_geo) is available upon request. All files from ./data_geo have been deposited in GEO, and files from ./data can be obtained from cBioPortal (https://www.cbioportal.org/), TCGA GDC ... |
| نوع الوثيقة: |
other/unknown material |
| اللغة: |
English |
| Relation: |
https://doi.org/10.5281/zenodo.6904027; https://doi.org/10.5281/zenodo.6904028; oai:zenodo.org:6904028 |
| DOI: |
10.5281/zenodo.6904028 |
| الاتاحة: |
https://doi.org/10.5281/zenodo.6904028 |
| Rights: |
info:eu-repo/semantics/openAccess ; Creative Commons Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/legalcode |
| رقم الانضمام: |
edsbas.87E41900 |
| قاعدة البيانات: |
BASE |