Furthermore, PI3K AKT sig naling, and ETV1 and ETV4 expression can both promote

We show that AKT activation is required for oncogenic ETS proteins to increase transcription of genes critical for cellular migration a pathway that pro motes progression of a neoplasia to an adenocarcinoma. Interestingly, in cells lacking oncogenic ETS expression, these genes are activated by the KU-0063794 938440-64-3 RAS ERK pathway through enhancer ETS AP 1 binding motifs, and are likely activated by mutations in this pathway in other cancers. We show that oncogenic ETS protein expres sion replaces RAS ERK regulation of these genes with PI3K AKT regulation. Our results are consistent with a recent finding that in mice the over expression of ERG in prostate epithelia only results in significant changes in gene expression when PTEN is deleted.<br><br> Together these findings provide an explanation for why the PI3K AKT pathway is activated more often than the RAS ERK pathway in prostate cancers, but not in other carcinomas that lack ETS gene fusions. We provide the first comprehensive analysis of onco genic Lenalidomide 404950-80-7 ETS, pERK and pAKT protein levels in prostate cancer cell lines. These results indicate that commonly used prostate cancer cell lines recapitulate patterns of oncogenic ETS expression observed in tu mors, such as a positive correlation between oncogenic ETS expression and PI3K AKT pathway activation, and negative correlation between oncogenic ETS expression and RAS ERK pathway mutations. CWR22Rv1 provided one exception to these correlations, as it expressed ETV4, pERK, and pAKT. This may reflect a unique role for ETV4, since a recent report indicates that expression of ETV4, but not other oncogenic ETS genes correlates with both PI3K and RAS signaling in prostate tumors.<br><br> Prostate tumors rarely have multiple ETS gene re LY2603618 分子量 arrangements, leading to the hypothesis that onco genic ETS genes have overlapping functions and therefore there is no advantage to the tumor to express more than one. Figure 1 indicates that oncogenic ETS proteins, even when expressed in a fusion independent manner, show the same pattern, supporting this redundancy model. This analysis also revealed that ERG expression strongly in creased pAKT levels, which may provide a positive feedback loop by increasing ERG function. This contrasts with findings in mice, where ERG did not increase pAKT. It may be that the effect of ERG on this pathway, and thus the necessity of PTEN deletion for increased pathway activation, varies by cellular back ground.<br><br> In summary, the cell line profiling presented here provides a basis for using these lines to model the com plex crosstalk of oncogenic ETS expression and signaling in various prostate tumors. The requirement of AKT for transcriptional activation by an ETS factor is novel. This could be due to AKT dir ectly phosphorylating ETS or AP 1 at ETS AP 1 se quences. AKT is known to modify transcription factors, such as those from the FOXO family. It is also pos sible that AKT is working through downstream signaling factors. We have ruled out mTORC1, but AKT can mod ify many other signaling proteins. These AKT regulated proteins include a number of factors specific to neurons, such as the GABA A receptor, Huntingtin, and Ataxin1. Interestingly, one of the normal functions of the oncogenic ETS proteins ETV1 and ETV4 is to cause certain neurons to outgrow and invade the spinal cord during development.