Regulation of cyclin-dependent kinase 5 and p53 by ERK1/2 pathway in the DNA damage-induced neuronal death.
DNA damage is known to be an initiator of neuronal death in neurodegenerative conditions such as Parkinson's and Alzheimer's diseases. The mechanism linking DNA damage and neuronal death is not completely understood. Here, we delineate the mechanism by which neuronal death evoked by DNA damage is controlled. Using mouse cortical neurons and SH-SY5Y human neuroblastoma cells, we identify a critical role of ERK signaling in neuronal death induced by DNA damage upon mitomycin C treatment. In addition, we provide evidence that the ERK signaling regulates Cyclin-dependent kinase 5 (Cdk5) activity and stability of tumor suppressor p53. Mitomycin C increased expression of p35, a specific activator of neuronal Cdk5 in an ERK1/2-dependent manner. Moreover, stability of p53 was increased by its phosphorylation on Ser33 and Ser46 by Cdk5, leading to neuronal death. Finally, we show that activated ERK induced increased expression of the Egr-1 transcription factor, which then bound to the promoter region of p35. We suggest subsequent increase of p35 expression and Cdk5 activity contribute to p53-dependent neuronal death. Thus, the present finding provides a new insight into a molecular mechanism underlying DNA damage-induced neuronal death.
Lee
Jong-Hee
JH
Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
Kim
Kyong-Tai
KT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016685:Mitomycin / Q000494:pharmacology; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010770:Phosphotransferases / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
C492236:Cdk5r1 protein, mouse; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D019384:Nucleic Acid Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D048052:Mitogen-Activated Protein Kinase 3