Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity

Cell Rep. 2024 Jun 25;43(6):114337. doi: 10.1016/j.celrep.2024.114337. Epub 2024 Jun 9.

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.

Keywords: CP: Cancer; CP: Metabolism; cancer metabolism; cancer mouse model of p53 activation; cancer protection; in vivo physiology in cancer; mevalonate pathway suppression; obesity and cancer; overweight and cancer; p53 activation; p53 derepression; p53 inhibitor; type 2 diabetes and cancer.

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Glucose / metabolism
  • Humans
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • Tumor Suppressor Protein p53
  • Glucose