The activation loop phosphorylation of protein kinase D is an early marker of neuronal DNA damage.
In neurons, DNA damage induces protein synthesis-dependent apoptosis mediated by the mitochondrial intrinsic cell-death pathway. Signal transduction cascades activated by genotoxic stress upstream of the mitochondria are largely unknown. We identified protein kinase D (PKD) as one of the earliest markers of neuronal DNA damage. Phosphorylation of the PKD-activation domain could be detected within 15 min of genotoxic stress and was concurrent with ataxia telangiectasia-mutated (ATM) activation. PKD stimulation was selective to DNA damage and did not occur with other stress stimuli examined. In vivo, both young and adult rats showed increased levels of phosphorylated PKD in neuronal tissues after injection of DNA-toxin etoposide. These results indicate that PKD activation is an early neuronal response to DNA damage, suggesting that signaling downstream of PKD may be critical for neuronal survival after genotoxic stress.
Besirli
Cagri G
CG
Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, USA.
Johnson
Eugene M
EM
D000818:Animals; D000831:Animals, Newborn; D064007:Ataxia Telangiectasia Mutated Proteins; D015415:Biomarkers / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D009474:Neurons / Q000473:pathology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D015415:Biomarkers; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C089212:protein kinase D; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C