Regulation of c-Myc through Phosphorylation at Ser-62 and Ser-71 by c-Jun N-Terminal Kinase

The expression of c-myc promotes cell proliferation and also sensitizes cells to various extracellular apoptotic stimuli. However, signal pathways regulating the function of Myc proteins during apoptosis are unknown. c-Jun N-terminal kinase (JNK) is activated by various apoptotic stimuli, but neithe...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-11, Vol.274 (46), p.32580-32587
Main Authors: Noguchi, Kohji, Kitanaka, Chifumi, Yamana, Hironobu, Kokubu, Akiko, Mochizuki, Toshihiro, Kuchino, Yoshiyuki
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Apoptosis
c-myc gene
c-Myc protein
Gene Expression Regulation
HeLa Cells
Humans
JNK Mitogen-Activated Protein Kinases
JNK protein
Mice
Mitogen-Activated Protein Kinases - metabolism
Mutagenesis
Paclitaxel - pharmacology
Phosphorylation
Protein Binding
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Recombinant Fusion Proteins
Signal Transduction
Ultraviolet Rays
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Summary:The expression of c-myc promotes cell proliferation and also sensitizes cells to various extracellular apoptotic stimuli. However, signal pathways regulating the function of Myc proteins during apoptosis are unknown. c-Jun N-terminal kinase (JNK) is activated by various apoptotic stimuli, but neither the target molecule(s) or the action of JNK has been identified in Myc-mediated apoptosis. Here, we found that JNK selectively interacted with, and phosphorylated, c-Myc at Ser-62 and Ser-71 as confirmed with phospho-c-Myc-specific antibodies. Interestingly, dominant negative mutant JNK(APF) impaired the c-Myc-dependent apoptosis, but not mutated c-Myc (S62A/S71A)-dependent apoptosis triggered by UV irradiation. Furthermore, c-Myc (S62A/S71A)-expressing NIH3T3 cells were not sensitized like wild type c-Myc-expressing NIH3T3 cells to JNK-activating apoptotic stimuli, such as UV and Taxol. These results indicate that the JNK pathway is selectively involved in the c-Myc-mediated apoptosis and that the apoptotic function of c-Myc is directly regulated by JNK pathway through phosphorylation at Ser-62 and Ser-71.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.46.32580