Ataxia-Telangiectasia Mutated Activation Mediates Transforming Growth Factor Beta Signaling in Acetaminophen-Induced Liver Injury in Mice

Authors

• Matthew McMillin
• Christopher S Chu
• Elaina Williams
• Juliet Venter
• Kiersten Bell
• Anca D Petrescu
• Patrick Mireles
• Sharon DeMorrow

Language

English

Publication Date

12-1-2025

Journal

Physiological Reports

DOI

10.14814/phy2.70695

PMID

41366830

PMCID

PMC12689461

PubMedCentral® Posted Date

12-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Acetaminophen (APAP) overdose is associated with increased transforming growth factor beta 1 (TGFβ1) signaling and elevated oxidative stress, which exacerbate DNA damage. TGFβ1 has been shown to regulate ataxia-telangiectasia mutated (ATM) signaling and DNA repair in other cell types. This study investigates the DNA damage response (DDR) during APAP-induced liver injury, focusing on ATM-mediated regulation of TGFβ1 signaling. APAP administration in vitro and in vivo resulted in DNA damage, increased ATM signaling, accumulation of γH2AX, and activation of phosphorylated ataxia telangiectasia mutated (pATM) and phosphorylated checkpoint kinase 2 (pChk2). Pretreatment with an ATM inhibitor, KU55933, attenuated APAP-induced hepatocyte damage and resulted in attenuated mothers against decapentaplegic homolog 2/3 (SMAD2/3) signaling with no changes in activated TGFβ1 levels, suggesting that ATM activation modulates TGFβ1 signaling via post-translational mechanisms. APAP was found to promote transforming growth factor beta receptor 2 (TGFβRII) stabilization through activation of phosphorylated casitas B-lineage lymphoma (p-c-cbl) and subsequent neddylation of TGFβRII, which was attenuated by inhibitors of ATM signaling or neddylation machinery. In conclusion, APAP-induced hepatic DNA damage activates an ATM-mediated response that enhances TGFβ1 signaling through stabilization of TGFβRII, and inhibition of ATM consequently reduces APAP-induced hepatic injury.

Keywords

Animals, Ataxia Telangiectasia Mutated Proteins, Acetaminophen, Signal Transduction, Mice, Chemical and Drug Induced Liver Injury, DNA Damage, Male, Transforming Growth Factor beta1, Mice, Inbred C57BL, Hepatocytesm, acute liver injury, DNA damage, DNA damage response, KU55933, SMAD signaling

Published Open-Access

yes

Recommended Citation

McMillin, Matthew; Chu, Christopher S; Williams, Elaina; et al., "Ataxia-Telangiectasia Mutated Activation Mediates Transforming Growth Factor Beta Signaling in Acetaminophen-Induced Liver Injury in Mice" (2025). Faculty and Staff Publications. 6.
https://digitalcommons.library.tmc.edu/huffington_pub/6