Abstract
Extracellular signal-regulated kinase 5 (ERK5), the newest member of the mitogen-activated protein (MAP) kinase family, is regulated differently than the other MAP kinases. Emerging evidence suggest the role of ERK5 signaling in promoting cell proliferation, differentiation, neuronal survival, and neuroprotection. The present study investigates whether suicide brain is associated with alterations in components of the ERK5 signaling cascade. In the prefrontal cortex (PFC) and hippocampus of suicide subjects (n=28) and nonpsychiatric control subjects (n=21), we examined the catalytic activities and protein levels of ERK5 and upstream MAP kinase kinase MEK5 in various subcellular fractions; mRNA levels of ERK5 in total RNA; and DNA-binding activity of myocyte enhancer factor (MEF)2C, a substrate of ERK5. In the hippocampus of suicide subjects, we observed that catalytic activity of ERK5 was decreased in cytosolic and nuclear fractions, whereas catalytic activity of MEK5 was decreased in the total fraction. Further, decreased mRNA and protein levels of ERK5, but no change in protein level of MEK5 were noted. A decrease in MEF2C-DNA-binding activity in the nuclear fraction was also observed. No significant alterations were noted in the PFC of suicide subjects. The observed changes were not related to a specific psychiatric diagnosis. Our findings of reduced activation and/or expression of ERK5 and MEK5, and reduced MEF2C-DNA-binding activity demonstrate abnormalities in ERK5 signaling in hippocampus of suicide subjects and suggest possible involvement of this aberrant signaling in pathogenic mechanisms of suicide.
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Acknowledgements
This research was supported by NIMH R0168777 to Dr Y Dwivedi, NIMH RO1MH48153 to Dr GN Pandey, and NIMH R01MH60744 to Dr R Roberts. We have no other financial or conflict of interest to disclose. We thank Miljana Petkovic and Barbara Brown for their help in organizing the brain tissue. We also thank the members of the Maryland Brain Collection for their efforts, particularly in family interviews and dissection. We are grateful for the cooperation of the Office of the Chief Medical Examiner in Baltimore, Maryland.
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Dwivedi, Y., Rizavi, H., Teppen, T. et al. Aberrant Extracellular Signal-Regulated Kinase (ERK) 5 Signaling in Hippocampus of Suicide Subjects. Neuropsychopharmacol 32, 2338–2350 (2007). https://doi.org/10.1038/sj.npp.1301372
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DOI: https://doi.org/10.1038/sj.npp.1301372
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