Functions of JNK stresskinases in neuronal apoptosis and differentiation

Eminel, Sevgi

The c-Jun N-terminal kinases (JNKs), a subfamily of the mitogen-activated protein kinases (MAPKs), are considered as essential signalling molecules for neurodegeneration in the mammalian brain. However, they also have physiological functions such as in development, differentiation, proliferation and neuroregeneration. The aims of the present study were to determine the physiological and pathological roles of JNK isoforms in PC12 cells and in primary neurons. 6-OHDA enhanced total JNK activity in the cytoplasm, nucleus and at the mitochondria in PC12 cells. Inhibition of JNKs by SP600125 or transfection with dominant negative JNK2 (dnJNK2) but not dnJNK1, substantially attenuated 6-OHDA-induced cell death. JNK2 translocated into the nucleus and mitochondria following 6-OHDA and mediates cytochrome c release and caspase-3 activation. In primary neurons JNKs also mediate death. Glutamate and 6-OHDA induced death and caspase-3 activation in primary hippocampal and cortical neurons, respectively. Inhibition of JNKs with SP600125 rescued these otherwise dying cells and inhibited caspase-3 activation, indicating JNK-mediated death. Besides neurodegenerative and pro-apoptotic functions, the family of JNKs has also been implicated in neuronal differentiation and development. Therefore the role of JNKs in neuronal differentiation were also analysed in this study. Inhibition of JNKs by SP600125 prevented neurite elongation in primary hippocampal neurons. These results provide evidence that JNKs have apoptotic effects after an excitotoxic stimulus but in parallel to their apoptotic effects they have also physiological functions on neurite formation and elongation in vitro during neuritogenesis.



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Eminel, Sevgi: Functions of JNK stresskinases in neuronal apoptosis and differentiation. 2007.


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