This indicates a crucial role for tissue context and the surrounding micro environment in determining cell fate. The divergence of MYC induced phenotypes between these two tissues has enabled us to compare MYC regu lated gene expression patterns over a time course of MYC ERTAM activation, by employing high throughput transcriptome analysis using microarrays. Comparison of the transcriptional response between the two tissues identified potential signalling pathways which may pro mote apoptosis of b cells and prevent apoptosis in SBK, the DNA damage response pathway, and the Insulin like growth factor 1 signalling pathway, Inhibitors,Modulators,Libraries respectively. In addition, up regulation of angiogenesis related genes and of those encoding members of the steroid hormone regu lated Kallikrein serine protease family was found in SBK but not in b cells.

Kallikreins may increase availability and action of Igf1 through proteolysis Inhibitors,Modulators,Libraries of Igf1 binding proteins. Together with angiogenesis, Kallikreins may provide a local tissue specific regulatory mechanism for determining ultimate MYC function in vivo. Results and Discussion Activation of MYC ERTAM mediates transcription of genes involved in a wide range of cellular functions Time courses were set up following activation of MYC in b cells and SBK via administration of 4 hydroxytamoxifen for 4 hrs, 8 hrs, 16 hrs and 32 hrs as described. Vehicle treated sam ples acted as direct time point controls for 4OHT trea ted samples. Laser capture microdissection was utilized to allow isolation of pancreatic islet tissue.

Sig nificant gene expression changes for the main experimental conditions and their interactions, as well as information on the effects of further covariates such as batch effects AV-951 and RNA quality, were identified using a custom R package, Envisage. Analysis of gene expression for 12,349 curated probe sets identified 6,633 unique genes as being significantly altered following activation of MYC with a false discovery rate of 5%. 1,615 genes showed signifi cant effects for the joint effects of 4OHT treatment, time and tissue type, 2,015 genes showed significant effects for the interaction between 4OHT treatment and tissue type, 2,221 genes showed significant effects for the interaction between 4OHT treatment and time, and 1,843 genes showed significant effects for the main effect of 4OHT treatment only.

Of the MYC responsive genes, the expression levels of 1,199 were altered greater than 2 fold after only 4 hours of 4OHT treatment for the pancreatic b cells, while only 530 were similarly affected for SBK. However, at 8 hours following initial 4OHT treatment, Inhibitors,Modulators,Libraries the expression Inhibitors,Modulators,Libraries levels of 1,905 and 1,882 were altered greater than 2 fold for the pancreas and the skin respectively. This suggests a more prominent initial response to MYC in b cells compared to SBKs.