Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity

It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR...

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Published inCell reports (Cambridge) Vol. 43; no. 6; p. 114337
Main Authors Tsaousidou, Eva, Chrzanowski, Jędrzej, Drané, Pascal, Lee, Grace Y., Bahour, Nadine, Wang, Zeqiu Branden, Deng, Shijun, Cao, Zhe, Huang, Kaimeng, He, Yizhou, Kaminski, Mateusz, Michalek, Dominika, Güney, Ekin, Parmar, Kalindi, Fendler, Wojciech, Chowdhury, Dipanjan, Hotamışlıgil, Gökhan S.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 25.06.2024
Elsevier
Subjects
Adipose Tissue - metabolism
Animals
cancer metabolism
cancer mouse model of p53 activation
cancer protection
Carcinogenesis - metabolism
Carcinogenesis - pathology
CP: Cancer
CP: Metabolism
Glucose - metabolism
Humans
in vivo physiology in cancer
Insulin Resistance
Male
mevalonate pathway suppression
Mice
Mice, Inbred C57BL
Mice, Knockout
obesity and cancer
overweight and cancer
p53 activation
p53 derepression
p53 inhibitor
RNA-Binding Proteins - metabolism
Tumor Suppressor Protein p53 - metabolism
type 2 diabetes and cancer
obesity and cancer
cancer protection
type 2 diabetes and cancer
p53 derepression
p53 activation
CP: Metabolism
overweight and cancer
mevalonate pathway suppression
cancer mouse model of p53 activation
p53 inhibitor
in vivo physiology in cancer
cancer metabolism
CP: Cancer
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Abstract It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR’s oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis. [Display omitted] •TIRR, by inhibiting p53, has opposing roles in metabolic homeostasis and oncogenesis•TIRR-deficient mice are spontaneously overweight and insulin resistant•TIRR deletion improves p53HET mouse survival, and the oncoprotective effect is p53 dependent•Low TIRR correlates with enhanced survival in patients with p53 heterozygous carcinomas Tsaousidou et al. describe opposing roles for TIRR, an inhibitor of the tumor suppressor p53. TIRR loss in mice results in increased body weight and insulin resistance but protects from cancer. Similarly, low TIRR levels correlate with increased body mass index in patients with type 2 diabetes but increased survival in patients with various carcinomas.
AbstractList It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR’s oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.
It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR’s oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis. [Display omitted] •TIRR, by inhibiting p53, has opposing roles in metabolic homeostasis and oncogenesis•TIRR-deficient mice are spontaneously overweight and insulin resistant•TIRR deletion improves p53HET mouse survival, and the oncoprotective effect is p53 dependent•Low TIRR correlates with enhanced survival in patients with p53 heterozygous carcinomas Tsaousidou et al. describe opposing roles for TIRR, an inhibitor of the tumor suppressor p53. TIRR loss in mice results in increased body weight and insulin resistance but protects from cancer. Similarly, low TIRR levels correlate with increased body mass index in patients with type 2 diabetes but increased survival in patients with various carcinomas.
It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53 HET ) mouse survival and correlates with enhanced progression-free survival in patients with various p53 HET carcinomas. Finally, TIRR’s oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis. Tsaousidou et al. describe opposing roles for TIRR, an inhibitor of the tumor suppressor p53. TIRR loss in mice results in increased body weight and insulin resistance but protects from cancer. Similarly, low TIRR levels correlate with increased body mass index in patients with type 2 diabetes but increased survival in patients with various carcinomas.
It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.
It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53 ) mouse survival and correlates with enhanced progression-free survival in patients with various p53 carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.
ArticleNumber 114337
Author Fendler, Wojciech
Cao, Zhe
Huang, Kaimeng
Bahour, Nadine
Güney, Ekin
Kaminski, Mateusz
Chrzanowski, Jędrzej
Deng, Shijun
Wang, Zeqiu Branden
Chowdhury, Dipanjan
Hotamışlıgil, Gökhan S.
He, Yizhou
Parmar, Kalindi
Lee, Grace Y.
Drané, Pascal
Michalek, Dominika
Tsaousidou, Eva
AuthorAffiliation 6 Present address: Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
4 Department of General Surgery, Medical University of Lodz, 90-153 Lodz, Poland
5 Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
1 Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
2 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
3 Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland
7 Present address: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
8 Lead contact
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Issue 6
Keywords obesity and cancer
cancer protection
type 2 diabetes and cancer
p53 derepression
p53 activation
CP: Metabolism
overweight and cancer
mevalonate pathway suppression
cancer mouse model of p53 activation
p53 inhibitor
in vivo physiology in cancer
cancer metabolism
CP: Cancer
Language English
License This is an open access article under the CC BY-NC-ND license.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
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AUTHOR CONTRIBUTIONS
Conceptualization, E.T., D.C., and G.S.H.; methodology, E.T., J.C., and W.F.; investigation, E.T., J.C., P.D., Y.H., D.M., M.K., E.G., G.Y.L., K.H., S.D., Z.B.W., Z.C., and W.F.; visualization, E.T., J.C., and W.F.; funding acquisition, E.T., W.F., D.C., and G.S.H.; project administration, K.P., W.F., D.C., and G.S.H.; supervision, D.C. and G.S.H.; writing – original draft, E.T.; writing – review & editing, E.T., J.C., P.D., Y.H., W.F., D.C., and G.S.H.
ORCID 0000-0003-2906-1897
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Snippet It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of...
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StartPage 114337
SubjectTerms Adipose Tissue - metabolism
Animals
cancer metabolism
cancer mouse model of p53 activation
cancer protection
Carcinogenesis - metabolism
Carcinogenesis - pathology
CP: Cancer
CP: Metabolism
Glucose - metabolism
Humans
in vivo physiology in cancer
Insulin Resistance
Male
mevalonate pathway suppression
Mice
Mice, Inbred C57BL
Mice, Knockout
obesity and cancer
overweight and cancer
p53 activation
p53 derepression
p53 inhibitor
RNA-Binding Proteins - metabolism
Tumor Suppressor Protein p53 - metabolism
type 2 diabetes and cancer
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Title Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity
URI https://dx.doi.org/10.1016/j.celrep.2024.114337
https://www.ncbi.nlm.nih.gov/pubmed/38861384
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https://pubmed.ncbi.nlm.nih.gov/PMC11325268
https://doaj.org/article/c830c19e952a4a9ebd6b580b85dca154
Volume 43
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