Equivalent to our final results it’s previously been reported that FoxO3a can activate Puma transcription and apoptosis in cytokine deprived lymphoid cells . The nuclear localization and transcriptional activity of FoxO3a is negatively regulated by AKT mediated phosphorylation. Consistent with this we located that IGF one prevented the potassium deprivation induced decrease in AKT activity, FoxO3a dephosphorylation and attenuated Puma induction. Interestingly, we located that inhibition of both JNK or GSK3b also inhibited FoxO3a dephosphorylation activation. These outcomes had been surprising provided that GSK3b is activated downstream of AKT and that JNK signaling won’t seem to impact AKT activity in this context . This suggests that JNK and GSK3b can regulate FoxO3a phosphorylation by an indirect mechanism or via an AKT independent mechanism maybe by regulating the exercise of a phosphatase involved in FoxO3a dephosphorylation.
Despite the fact that JNK and GSK3b were found to impact FoxO3a activation we cannot rule out the possibility that they may well also regulate other transcription factors involved with Puma induction. A candidate issue downstream of GSK3b is nuclear aspect of activated T cells which has been shown to become phosphorylated by GSK3b resulting in its export in the nucleus and promotion of survival in CGNs SB 203580 . In this instance NFAT could act as being a repressor of Puma transcription which is removed on GSK3b activation. Similarly, beta catenin may perhaps be acting to suppress Puma induction until eventually inactivated by GSK3b. Phosphorylation of beta catenin by GSK3b leads to its translocation from the nucleus and targets it for degradation and inhibition of this phosphorylation event has become related with neuronal survival .
Ultimately, there are many downstream targets from the JNK pathway which could control Puma expression following Maraviroc JNK activation, these incorporate c Jun, activating transcription aspect two and activating transcription element three . A foremost downstream target of JNK, c Jun has become noticed to become upregulated in trophic aspect deprived neurons and ectopic expression of dominant adverse c Jun was uncovered to safeguard against cell death . The JNK regulated transcription factors ATF2 and ATF3 can also be induced in response to potassium deprivation and it’s been reported that knockdown or inhibition of those variables can protect neurons against apoptosis . It will be noteworthy the Puma promoter is made up of putative AP1 binding web-sites which are the identified target sequence for all three of these transcription elements, suggesting a probable function for these factors in Puma induction.
Interestingly, a current research implicated c Jun while in the regulation of Puma expression in fatty acid induced apoptosis of hepatocytes , though the AP one binding internet site identified on this examine will not seem for being conserved.