Related Experiment Video

Updated: Jun 24, 2025

Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

9.5K

Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity

Eva Tsaousidou1, Jędrzej Chrzanowski2, Pascal Drané3

  • 1Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Cell Reports
|June 11, 2024
PubMed

Insights

Deleting Tudor-interacting repair regulator (TIRR) activates the tumor suppressor p53, reducing cancer but causing metabolic issues like obesity and insulin resistance. This highlights a trade-off between cancer protection and metabolic health.

Area of Science:

  • Oncology
  • Metabolic Health
  • Molecular Biology

Background:

  • The relationship between metabolic health and oncogenesis is not fully understood.
  • Tudor-interacting repair regulator (TIRR) is identified as an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation.
  • Investigating TIRR's role offers insights into tumor suppression and metabolic regulation.

Purpose of the Study:

  • To investigate the physiological consequences of enhancing tumor suppressor activity by modulating TIRR.
  • To determine the impact of TIRR deletion on cancer development and metabolic health in vivo and in human tissues.
  • To elucidate the dependency of TIRR's oncoprotective and metabolic effects on p53.

Main Methods:

  • Utilized genetic deletion of TIRR in mice to study its effects on p53 activation, cancer protection, and metabolic parameters.
  • Assessed metabolic health, including body weight and insulin resistance, in TIRR-deficient mice on a standard diet.
  • Correlated TIRR expression with BMI and insulin resistance in human adipose tissue samples.
  • Employed tissue-specific models to investigate the roles of adipose tissue and the central nervous system (CNS) in regulating glucose homeostasis and orexigenesis.

Main Results:

  • TIRR deletion selectively activates p53, conferring significant protection against cancer.
  • TIRR-deficient mice exhibit systemic metabolic imbalance, characterized by overweight and insulin resistance.
  • Reduced TIRR expression in human adipose tissue correlates with increased BMI and insulin resistance.
  • Loss of TIRR improves survival in p53 heterozygous (p53HET) mice and correlates with enhanced progression-free survival in patients with p53HET carcinomas.
  • Both oncoprotective and metabolic effects of TIRR are dependent on p53, as they are abolished upon p53 deletion in TIRR-deficient mice.
  • Adipose tissue and CNS primarily regulate glucose homeostasis and orexigenesis, respectively, in response to TIRR expression.

Conclusions:

  • TIRR deletion represents a novel paradigm linking metabolic deregulation with reduced oncogenesis.
  • Modulating TIRR offers a potential therapeutic strategy for cancer, but its impact on metabolic health must be carefully considered.
  • The findings underscore the intricate interplay between tumor suppression pathways and systemic metabolic regulation.
Keywords:
CP: CancerCP: Metabolismcancer metabolismcancer mouse model of p53 activationcancer protectionin vivo physiology in cancermevalonate pathway suppressionobesity and canceroverweight and cancerp53 activationp53 derepressionp53 inhibitortype 2 diabetes and cancer

More Related Videos

Using Mouse Mammary Tumor Cells to Teach Core Biology Concepts: A Simple Lab Module10:39

Using Mouse Mammary Tumor Cells to Teach Core Biology Concepts: A Simple Lab Module

Published on: June 18, 2015

13.1K
An Orthotopic Murine Model of Human Prostate Cancer Metastasis06:48

An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

35.1K

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.5K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.5K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.5K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.7K