Abstract
The AKT, GSK3 and JNK family kinases have been implicated in neuronal apoptosis associated with neuronal development and several neurodegenerative conditions. However, the mechanisms by which these kinase pathways regulate apoptosis remain unclear. In this study we have investigated the role of these kinases in neuronal cell death using an established model of trophic factor deprivation induced apoptosis in cerebellar granule neurons. BCL-2 family proteins are known to be central regulators of apoptosis and we have determined that the pro-apoptotic family member Puma is transcriptionally up-regulated in trophic factor deprived neurons and that Puma induction is required for apoptosis in vitro and in vivo. Importantly, we demonstrate that Puma induction is dependent on both JNK activation and AKT inactivation. AKT is known to regulate a number of downstream pathways, however we have determined that PI3K-AKT inactivation induces Puma expression through a GSK3β-dependent mechanism. Finally we demonstrate that the JNK and AKT/GSK3β pathways converge to regulate FoxO3a-mediated transcriptional activation of Puma. In summary we have identified a novel and critical link between the AKT, GSK3β and JNK kinases and the regulation of Puma induction and suggest that this may be pivotal to the regulation of neuronal apoptosis in neurodegenerative conditions.
Highlights
Apoptosis is a form of programmed cell death that is required in many physiological processes such as embryogenesis, cell turnover and response to pathogens
In cerebellar granule neurons (CGNs) apoptosis induced by potassium withdrawal can be prevented by actinomycin-D or cycloheximide suggesting that de novo transcription is critical to the initiation of apoptosis and likely to the activation of BH3-only proteins [43]
As Bim has been implicated in neuronal apoptosis induced by trophic factor deprivation [71,72], we examined the level of apoptosis in CGNs derived from Bim-null mice following potassium deprivation
Summary
Apoptosis is a form of programmed cell death that is required in many physiological processes such as embryogenesis, cell turnover and response to pathogens. Kinase signaling pathways play a key role in signal transduction in all cellular processes including apoptosis. The JNK pathway is pro-apoptotic and JNK itself is known to be activated in several models of neuronal apoptosis including excitotoxicity, trophic factor withdrawal and ischemia (reviewed in [9]). GSK3b has been found to play a pro-apoptotic role in several models of neuronal cell death including serum deprivation, DNA damage and Ab induced toxicity [14,15,16]. While inhibition of GSK3 promotes cell survival, overexpression of active GSK3b has been shown to promote neuronal apoptosis [17]. While the JNK-, GSK3band AKT- pathways have been established as key players in neuronal apoptosis, the downstream targets that link these kinases to the apoptotic machinery has not been clearly defined
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