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The c-Jun N-terminal kinase 1 activity is differentially regulated by specific mechanisms during apoptosis

Young-Mi Ham1, Joon-Seok Choi, Kwang-Hoon Chun

  • 1Division of Pharmaceutical Biosciences, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Korea.

The Journal of Biological Chemistry
|September 30, 2003
PubMed

Insights

JNK1 activation has two phases during apoptosis. The later phase, dependent on caspases and PKC-delta, drives cell death, while the early phase does not directly cause apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Apoptosis, or programmed cell death, is crucial for development and disease.
  • JNK1 (c-Jun N-terminal kinase 1) is a key signaling molecule implicated in stress responses and apoptosis.
  • Understanding the specific roles of JNK1 activation phases in apoptosis is vital for therapeutic development.

Purpose of the Study:

  • To elucidate the distinct roles of early and late phases of JNK1 activation in paclitaxel- or ginsenoside-Rh2-induced apoptosis.
  • To identify the molecular mechanisms governing these JNK1 activation phases and their contribution to apoptotic progression.

Main Methods:

  • Utilized dominant-negative SEK1 and p21(WAF1/CIP1) mutants to perturb JNK1 activation pathways.
  • Employed rottlerin (PKC-delta inhibitor) and z-VAD-fmk (pan-caspase inhibitor) to investigate downstream effectors.
  • Assessed apoptosis induction and suppression using JNK1-expressing cells, dominant-negative JNK1 (DN-JNK1), and JNK inhibitor protein (JBD).

Main Results:

  • Early JNK1 activation, mediated by SEK1, did not prevent apoptosis.
  • Late JNK1 activation, coinciding with caspase-dependent p21(WAF1/CIP1) cleavage and requiring PKC-delta activity, was essential for apoptosis.
  • Inhibition of late JNK1 activation or caspase activity prevented apoptosis, while JNK1 overexpression promoted it.

Conclusions:

  • The later phase of JNK1 activation is a critical mediator of apoptosis induction through a caspase- and PKC-delta-dependent pathway.
  • The early phase of JNK1 activation is not directly involved in the apoptotic process.
  • Targeting the late JNK1 activation pathway offers a potential strategy for controlling apoptosis in cancer therapy.

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