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Deregulated JNK signaling enhances apoptosis during hyperthermia

Atsushi Enomoto1, Takemichi Fukasawa2,3, Hiroshi Terunuma4

  • 1Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
|April 2, 2024
PubMed
Abstract

Insights

Heat activates c-Jun N-terminal kinases (JNK) by decreasing DUSP16, a JNK phosphatase. This leads to the activation of the ASK1-SEK1-JNK pathway and subsequent apoptosis, even with reduced upstream signaling.

Area of Science:

  • Cellular stress response
  • Signal transduction pathways
  • Apoptosis regulation

Background:

  • c-Jun N-terminal kinases (JNKs), a subfamily of mitogen-activated protein kinases (MAPKs), are activated by various stimuli.
  • The precise molecular mechanisms of heat-induced JNK activation remain largely unelucidated.
  • Understanding heat-induced JNK activation is crucial for comprehending cellular responses to thermal stress.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying heat-induced activation of JNK.
  • To investigate the role of upstream MAP kinase members and phosphatases in this process.
  • To clarify the pathway leading to JNK activation under hyperthermia.

Main Methods:

  • Western blotting to evaluate MAPK expression levels in HeLa cells under hyperthermia.
  • In vitro kinase assays to assess the activity of MAPK members.
  • siRNA-mediated knockdown to investigate the role of specific MAPK members and DUSP16 in cell death.

Main Results:

  • Hyperthermia decreased MAP3K levels (ASK1, MLK3) but not downstream MAP2K/SEK1 or MAPK/JNK.
  • JNK phosphorylation occurred in a temperature-dependent manner, independent of upstream MAP3K/MAP2K phosphorylation.
  • Reduced DUSP16 expression upon hyperthermia correlated with enhanced JNK activation and apoptosis.

Conclusions:

  • JNK activation by heat is temperature-dependent and occurs despite reduced upstream signaling.
  • Hyperthermia-induced degradation of DUSP16 is a key event that activates the ASK1-SEK1-JNK pathway.
  • This pathway activation contributes to heat-induced apoptosis.
Keywords:
DUSP16HyperthermiaJNK signalingapoptosisdegradationphosphorylation

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