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Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase

K Noguchi1, C Kitanaka, H Yamana

  • 1Biophysics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

The Journal of Biological Chemistry
|November 7, 1999
PubMed

Insights

The c-Jun N-terminal kinase (JNK) pathway phosphorylates c-Myc, a key protein in cell proliferation, directly regulating its apoptotic function. This phosphorylation is crucial for Myc-mediated apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • c-Myc protein promotes cell proliferation and sensitizes cells to apoptosis.
  • Signaling pathways regulating Myc protein function during apoptosis remain largely unknown.
  • c-Jun N-terminal kinase (JNK) is activated by apoptotic stimuli, but its role in Myc-mediated apoptosis is unclear.

Purpose of the Study:

  • To investigate the signaling pathways regulating Myc protein function during apoptosis.
  • To identify the role of c-Jun N-terminal kinase (JNK) in Myc-mediated apoptosis.
  • To elucidate the molecular mechanism by which JNK influences c-Myc's apoptotic activity.

Main Methods:

  • Utilized phospho-c-Myc-specific antibodies to confirm JNK interaction and phosphorylation of c-Myc at Ser-62 and Ser-71.
  • Employed dominant-negative JNK (JNK(APF)) mutants to assess the impact on c-Myc-dependent apoptosis.
  • Generated and analyzed NIH3T3 cells expressing wild-type or mutated c-Myc (S62A/S71A) to evaluate sensitization to apoptotic stimuli.

Main Results:

  • Demonstrated that JNK selectively interacts with and phosphorylates c-Myc at specific serine residues (Ser-62 and Ser-71).
  • Showed that dominant-negative JNK impaired c-Myc-dependent apoptosis, while mutated c-Myc (S62A/S71A) abrogated this effect.
  • Found that cells expressing mutated c-Myc were not sensitized to JNK-activating apoptotic stimuli (UV, Taxol) compared to wild-type c-Myc cells.

Conclusions:

  • The JNK pathway is selectively involved in c-Myc-mediated apoptosis.
  • JNK directly regulates the apoptotic function of c-Myc through phosphorylation at Ser-62 and Ser-71.
  • Phosphorylation of c-Myc by JNK is a critical step in sensitizing cells to apoptotic stimuli.

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