ISG12a and its interaction partner NR4A1 are involved in TRAIL-induced apoptosis in hepatoma cells

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Updated: Jan 28, 2026

Identification of Protein Interaction Partners in Mammalian Cells Using SILAC-immunoprecipitation Quantitative Proteomics
12:53

Identification of Protein Interaction Partners in Mammalian Cells Using SILAC-immunoprecipitation Quantitative Proteomics

Published on: July 6, 2014

32.0K

Nianli Liu1,2, Zhiyuan Wu1,2, Aoxing Chen1,2

  • 1Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Journal of Cellular and Molecular Medicine
|March 2, 2019
PubMed

Insights

ISG12a enhances cancer cell death induced by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL). This protein interacts with NR4A1, promoting apoptosis and potentially overcoming TRAIL resistance in cancer treatment.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Mechanisms

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for cancer therapy by selectively inducing apoptosis in cancer cells.
  • Clinical applications of TRAIL agonists are limited by a lack of predictive biomarkers for patient response and mechanisms of cancer cell resistance.
  • Previous research identified ISG12a as a potential biomarker that enhances TRAIL-induced apoptosis.

Purpose of the Study:

  • To elucidate the downstream mechanism by which ISG12a augments TRAIL-induced apoptosis.
  • To investigate the interaction between ISG12a and its downstream partners in the context of TRAIL signaling.
  • To explore the role of ISG12a and its interacting proteins in mediating TRAIL sensitivity and resistance in hepatoma cells.

Main Methods:

  • Subcellular localization studies of ISG12a.
  • Analysis of the intrinsic apoptotic pathway activation.
  • Co-immunoprecipitation to identify interacting proteins.
  • NR4A1 translocation assays and functional studies.
  • NF-κB and Jun N-terminal kinase signaling pathway analysis.
  • Gene knockdown experiments to assess functional significance.

Main Results:

  • ISG12a localizes to mitochondria and the nucleus, enhancing TRAIL-induced apoptosis via the intrinsic pathway.
  • ISG12a interacts with NR4A1, promoting its translocation from the nucleus to the cytoplasm.
  • Cytoplasmic NR4A1 targets mitochondria, induces Bcl2 conformational changes, and exposes the BH3 domain.
  • TRAIL induces NR4A1 expression via NF-κB activation in TRAIL-resistant cells, and NR4A1 knockdown overcomes this resistance.
  • TRAIL activates Jun N-terminal kinases in TRAIL-sensitive cells.

Conclusions:

  • ISG12a and NR4A1 are key mediators of TRAIL-induced apoptosis in hepatoma cells.
  • The ISG12a-NR4A1 interaction and subsequent NR4A1 cytoplasmic translocation are critical for augmenting TRAIL sensitivity.
  • Understanding these mechanisms provides insights into overcoming TRAIL resistance and developing targeted cancer therapies.
Keywords:
ISG12aNR4A1TRAIL resistanceapoptosisliver cancer

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