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Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay
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Long-term Activation of c-Jun N-terminal Kinase through Receptor Interacting Protein is Associated with DNA

Jeong Ho Seok1, Kyeong Ah Park, Hee Sun Byun

  • 1Department of Pharmacology, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-131, Korea.

The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology
|December 8, 2009
PubMed

Insights

Receptor interacting protein (RIP) mediates sustained c-Jun N-terminal kinase (JNK) activation by DNA damage, influencing cell death. This pathway, distinct from TNF signaling, requires ATM activity and is crucial for specific genotoxic stress responses.

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Stress response pathways

Background:

  • c-Jun N-terminal kinase (JNK) activation is a key cellular response to genotoxic stress and tumor necrosis factor (TNF).
  • The precise signaling pathways and cellular sensors initiating JNK activation under genotoxic stress remain largely unidentified.
  • Understanding these pathways is crucial for deciphering cell fate determination following DNA damage.

Purpose of the Study:

  • To identify the signaling molecules and pathways involved in JNK activation by DNA damaging agents.
  • To investigate the role of receptor interacting protein (RIP) and ATM in mediating JNK activation by different types of genotoxic stress.
  • To determine the contribution of sustained JNK activation to DNA damage-induced cell death.

Main Methods:

  • Treatment of cells with various DNA damaging agents (adriamycin, 1-beta-D-arabinofuranosylcytosine, N-methyl-N-nitro-N-nitrosoguanidine, UV light).
  • Assessment of JNK activation kinetics and dependence on RIP and ATM.
  • Inhibition of JNK using SP-600125 to evaluate its role in cell death.

Main Results:

  • Receptor interacting protein (RIP) is essential for sustained JNK activation by adriamycin and 1-beta-D-arabinofuranosylcytosine, but not by N-methyl-N-nitro-N-nitrosoguanidine or UV.
  • Sustained JNK activation by these agents is mediated by ATM (ataxia telangiectasia) activity, independent of TNF receptor signaling.
  • JNK inhibition blocked adriamycin-induced cell death but not N-methyl-N-nitro-N-nitrosoguanidine-induced cell death.

Conclusions:

  • Sustained JNK activation, mediated by RIP and ATM, plays a significant role in DNA damage-induced cell death.
  • The duration of JNK activation dictates the cellular response and fate following genotoxic stress.
  • This study elucidates a novel pathway for DNA damage signaling through RIP and ATM to JNK.
Keywords:
Cell deathDNA damagePoly (ADP-ribose) polymeraseReceptor interacting proteinc-Jun N-terminal kinase

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