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Updated: Feb 16, 2026

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates
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Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates

Published on: May 10, 2022

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FOXO3 induces ubiquitylation of AKT through MUL1 regulation

Sun-Yong Kim1, Hyo Jeong Kim1,2, Hyung Kwon Byeon3,4

  • 1Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea.

Oncotarget
|January 5, 2018
PubMed

Insights

Cisplatin triggers thyroid cancer cell death by activating the mitochondrial E3 ubiquitin ligase 1 (MUL1) and inhibiting AKT. This pathway, involving FOXO3 and reactive oxygen species (ROS), offers a new strategy for head and neck cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • AKT (protein kinase B) is crucial for cell survival and tumor progression, making it a key target in cancer therapy.
  • Mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is downregulated in head and neck cancer (HNC) and negatively regulates AKT.
  • Mechanisms controlling MUL1 function are not fully understood.

Purpose of the Study:

  • To investigate the role of the MUL1-AKT axis in cisplatin-induced thyroid cancer cell death.
  • To elucidate the regulatory mechanisms of MUL1, particularly the involvement of FOXO3 and reactive oxygen species (ROS).
  • To explore the potential of targeting the FOXO3-MUL1-AKT pathway for HNC treatment.

Main Methods:

  • Investigated cisplatin (CDDP) effects on thyroid cancer cells.
  • Analyzed the ubiquitylation of active AKT mediated by MUL1.
  • Examined the role of forkhead box O3 (FOXO3) and intracellular ROS in the CDDP-induced pathway.

Main Results:

  • CDDP treatment increases MUL1 expression, leading to ubiquitylation and inactivation of active AKT.
  • FOXO3 is essential for CDDP-induced MUL1 regulation; FOXO3 knockdown confers resistance to CDDP.
  • CDDP-induced intracellular ROS increment is a critical component of the FOXO3-MUL1-AKT signaling pathway.

Conclusions:

  • CDDP induces thyroid cancer cell death via the FOXO3-MUL1-AKT axis.
  • FOXO3 acts as a key regulator in this pathway, mediating MUL1's tumor-suppressive function.
  • Targeting the FOXO3-MUL1-AKT pathway presents a potential novel therapeutic strategy for HNC treatment with CDDP.
Keywords:
AKTFOXO3MUL1/MULAN/GIDEcisplatinubiquitylation

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