Related Experiment Video

Updated: Jun 4, 2025

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
08:19

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

Published on: July 20, 2019

5.9K

Nerve Growth Factor Signaling Promotes Nuclear Translocation of TRAF4 to Enhance Tumor Stemness and Metastatic

Kai Zhao1, Tifan Sun1, Qiruo Sun1

  • 1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 24, 2024
PubMed

Insights

Nuclear TRAF4 promotes tumor stemness and dormancy by interacting with c-Jun and upregulating IL-8. Targeting nuclear TRAF4 translocation offers a potential therapeutic strategy for metastatic cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Tumor necrosis factor receptor-associated factor 4 (TRAF4) is an E3 ubiquitin ligase overexpressed in tumors.
  • Its cytoplasmic functions are known, but its nuclear roles in cancer remain unclear.

Purpose of the Study:

  • To investigate the nuclear functions of TRAF4 in regulating tumor stemness and dormancy.
  • To elucidate the molecular mechanisms of TRAF4 nuclear translocation and its downstream effects.

Main Methods:

  • Correlation analysis of nuclear TRAF4 expression with tumor grade and stemness signatures.
  • TRAF4-knockout (TRAF4-KO) cell models to assess stemness and dormancy.
  • Co-immunoprecipitation to study protein interactions (TRAF4-c-Jun).
  • Reporter assays to measure promoter activity (IL-8).
  • Analysis of TRAF4 phosphorylation and nuclear translocation pathways (AKT, 14-3-3θ).
  • In vivo tumor models to evaluate therapeutic potential.

Main Results:

  • Nuclear TRAF4 expression positively correlates with tumor grade and stemness.
  • Reduced nuclear TRAF4 impairs tumor stemness and metastatic dormancy.
  • Nuclear TRAF4 interacts with c-Jun, enhancing IL-8 promoter activity.
  • AKT signaling-mediated phosphorylation of TRAF4 at Ser242 promotes its nuclear translocation.
  • Pharmacological inhibition of TRAF4 nuclear translocation reduces tumorigenicity and metastasis.

Conclusions:

  • Nuclear TRAF4 is a key regulator of tumor stemness and dormancy.
  • The TRAF4-c-Jun-IL-8 axis is critical for these processes.
  • TRAF4 nuclear translocation is a druggable target for treating metastatic and refractory cancers.
Keywords:
IL‐8TRAF4metastatic dormancynuclear translocationstemness

More Related Videos

A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth06:35

A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth

Published on: December 22, 2020

4.4K
Tumor Allotransplantation in Drosophila melanogaster with a Programmable Auto-Nanoliter Injector05:06

Tumor Allotransplantation in Drosophila melanogaster with a Programmable Auto-Nanoliter Injector

Published on: February 2, 2021

2.3K

Related Concept Videos

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...
3.7K
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.2K
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
7.2K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.4K
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
2.5K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.2K