There have been conflicting reports regarding the role of Akt in neuronal outgrowth/differentiation. Several studies download catalog have reported a negative impact of Akt upon neuronal dif ferentiation, while others published opposite results. The reason for this discrepancy is not known. The be envisioned from these results that Akt mediated down regulation of these genes of neuronal function is relevant to the diminished manifestation of neuronal phenotype Inhibitors,Modulators,Libraries in cells overexpressing Akt. Akt is often found activated in some neuroblastomas as well as many other human can cers. Neuroblastomas with hyperactive Akt or with low potential to differentiate in response to neurotrophins show poor prognosis. There might be a causal con nection between the Akt activity and the differentiation ability in these neuroblastomas.
We observed that incuba tion of PC12 cells with the Akt inhibitor AKTi 1/ 2 restored their neurite outgrowth responsiveness to NGF. In this respect, a use of an Akt inhibitor like AKTi 1/2 would be advantageous in that it can not only possess the cytotoxic effect but can also lead the cells to respond to the differentiation Inhibitors,Modulators,Libraries effect of neurotrophins. The mechanism of the downregulation of MafK, SytI, and Syn 1 genes by Akt remains unclear. However, the increased expression of MafK and Syn 1 genes in PC12 cells upon pharmacological inhibition of Gsk3B indicates that Gsk3B somehow regulates the tran scription factors for these two genes. Gsk3B phosphorylates Inhibitors,Modulators,Libraries several transcription factors, including AP 1, CREB, HSF 1, NFAT, C/EBP, and NF kB, Ngn2, and Smad3/4.
The functional consequence of this interaction with Gsk3B differs among transcription factors. While most are inhibited by Gsk3B, the transcriptional activity of C/EBP and Ngn2 is increased by Gsk3B. Since Akt phosphorylates and inhibits Gsk3B, Inhibitors,Modulators,Libraries the transcriptional activity of C/EBP and Ngn2 might be downregulated in PC12 cells but upregulated in PC12 cells. In this regard, it remains Inhibitors,Modulators,Libraries to be determined whether MafK and Syn 1 gene expressions are altered by expressing the active or domi nant negative form of C/EBP and Ngn2 in PC and PC cells, respectively. Our work indicates that the Gsk3B pathway does not appear to be implicated in the decreased expression of SytI in PC12. Expression of SytI in sympathetic neurons has been shown to be induced by BMP4, and BMP4 sig naling is known to be mediated by Smad proteins and MAPKs.
Therefore, it can be suggested that decreased expression of SytI in PC12 cells might be due to the Akt mediated inhibition of the Raf MAPK pathway. Alternatively, Akt might directly affect the tran scription factor responsible for SytI expression. This could be Brn3, because this is the only transcription factor identi fied so far that could increase the expression of SytI in neu ronal unless cells, and interestingly it has the preferred phosphorylation motif of Akt.
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