Early activation of c-Jun N-terminal kinase and p38 kinase regulate cell survival in response to tumor necrosis

Related Experiment Video

Updated: Oct 30, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

A Roulston1, C Reinhard, P Amiri

  • 1Chiron Technologies, Chiron Corporation, Emeryville, California 94608, USA. Anne_Roulston@cc.chiron.com

The Journal of Biological Chemistry
|May 30, 1998
PubMed

Insights

Tumor necrosis factor alpha (TNF) signaling activates stress kinases, including p38 kinase, which protect cells from TNF-induced apoptosis. Early p38 kinase activation is crucial for cell survival, while Mek inhibition has no effect.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Immunology

Background:

  • Fas ligand and tumor necrosis factor alpha (TNF) are members of the TNF receptor superfamily, initiating distinct cellular responses.
  • While both Fas and TNF signaling activate c-Jun N-terminal kinase (JNK) and p38 kinase pathways, their precise roles in apoptosis remain debated.
  • Fas-induced apoptosis is caspase-dependent, whereas TNF requires actinomycin D and exhibits biphasic kinase activation.

Purpose of the Study:

  • To investigate the role of early stress kinase activation in TNF-mediated apoptosis.
  • To differentiate the roles of JNK and p38 kinase in TNF signaling pathways.
  • To determine the impact of inhibiting specific kinase pathways on TNF-induced cell death.

Main Methods:

  • Utilized TNF stimulation in the presence of actinomycin D.
  • Employed MKK4/MKK6 mutants and SB203580 (p38 inhibitor) to block early kinase activation.
  • Assessed apoptosis and cell survival following kinase inhibition.
  • Investigated the effect of PD098059 (Mek inhibitor) on TNF-induced apoptosis.

Main Results:

  • TNF-induced JNK and p38 kinase activation occurs in two phases: a transient, caspase-independent early phase and a late, caspase-dependent phase.
  • Inhibition of early TNF-induced p38 kinase activation (using SB203580 or MKK4/MKK6 mutants) significantly increased TNF-induced apoptosis.
  • Conversely, expression of wild-type MKK4/MKK6 enhanced cell survival.
  • Inhibition of Mek with PD098059 did not affect TNF-induced apoptosis.

Conclusions:

  • Early activation of p38 kinase, but not Mek, is essential for protecting cells against TNF-mediated cytotoxicity.
  • The findings highlight a critical role for early stress kinase activation, particularly p38, in regulating TNF-induced apoptosis and promoting cell survival.

Related Concept Videos

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...
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...
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...
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 heterodimer of NF-κB...
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...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...