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Mitogen-activated protein kinase phosphatase-1 represses c-Jun NH2-terminal kinase-mediated apoptosis via NF-kappaB

Zhaoqing Wang1, Ning Cao, Danupon Nantajit

  • 1Division of Molecular Radiobiology, Purdue University School of Health Sciences, 550 Stadium Mall Drive, West Lafayette, IN 47907, USA.

The Journal of Biological Chemistry
|May 30, 2008
PubMed

Insights

Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 regulates cell survival after radiation. This study shows NF-kappaB induces MKP-1, which inhibits JNK-mediated apoptosis, offering a target to improve radiosensitivity.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Radiation Oncology

Background:

  • Radiation-induced apoptosis is crucial for cancer treatment but is often counteracted by anti-apoptotic mechanisms.
  • Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 is a key regulator of MAPK signaling pathways.
  • The precise role of MKP-1 in radiation-induced apoptosis remains incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism by which MKP-1 regulates radiation-induced anti-apoptotic responses.
  • To investigate the interplay between NF-kappaB, MKP-1, and JNK signaling in cellular radiosensitivity.

Main Methods:

  • Gamma-radiation treatment of cells and mouse embryonic fibroblasts.
  • Analysis of MKP-1 gene promoter activity and NF-kappaB binding.
  • Use of small interfering RNA (siRNA) to inactivate NF-kappaB and MKP-1.
  • Assessment of MAPK subfamily activation (JNK, p38, ERK) via Western blotting.
  • Rescue experiments involving MKP-1 overexpression.

Main Results:

  • Gamma-radiation induced MKP-1 expression, which repressed pro-apoptotic signaling.
  • NF-kappaB RelA/p50 heterodimers were recruited to the MKP-1 promoter, driving its transcription.
  • MKP-1 deficiency led to prolonged JNK activation, specifically inhibiting radiation-induced apoptosis.
  • Inactivation of MKP-1 in human tumor cells increased apoptosis, which was reversible by MKP-1 re-expression.

Conclusions:

  • MKP-1 acts as a prosurvival effector, mediating NF-kappaB's suppression of JNK-induced apoptosis following radiation.
  • The NF-kappaB/MKP-1 pathway negatively regulates JNK, impacting cellular radiosensitivity.
  • Targeting the NF-kappaB/MKP-1-JNK axis presents a potential therapeutic strategy to enhance cancer cell radiosensitivity.

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