p18Ink4c interacts directly with Atm Atr leading to an increase in p53 protein, and promotion of growth arrest and or cell death, suggesting a link between p18 Ink4c and the DNA damage Inhibitors,Modulators,Libraries response path ways. Comparatively few DNA damage related genes showed significant changes in expression for SBK, although we cannot exclude the possibility that DNA damage proteins may be regulated by MYC through non transcriptional means. Of particular interest was the survival factor gene Igf1, whose product has been shown to inhibit MYC induced apoptosis in vitro by blocking Cytochrome c release from the mitochondria through the Akt1 tumour sup pressor pathway. Igf1 was up regulated throughout much of the time course for SBK, and this was con firmed using qRT PCR.

Consistent with this finding, Akt1 was up regulated 3 fold at 8 hours and 2 fold at 32 hours. A similar pattern was observed for Akt2, a second member of the Akt protein kinase family. Inhibitors,Modulators,Libraries This strongly supports the view that activation of the Igf Akt pathway may contribute to suppression of MYC related apoptosis. Interestingly, Igf1, Akt1 and Akt2 were up regulated at later time points in b cells. It is therefore possible that the Igf Akt pathway is acti vated in both tissues, but that the b cells may be able to bypass these signals. The pro apoptotic Bcl2 family member Pmaip1 and the gene encoding inhibitor of growth pro tein p47Ing3 both showed a decrease in expression of 2 fold at 8 hours in SBK, but exhibited no change in b cells.

Over expression of p47Ing3 results in cell cycle Anacetrapib arrest and apoptosis in cancer cell lines, and reduced expression and loss of heterozygosity of the p47Ing3 locus have been found to be associated with human head and neck squamous carcinomas. Also seen were several members of the TNF Inhibitors,Modulators,Libraries superfamily of apoptosis inducing receptors. Tnfrsf12a, which has been found to be involved in inducing both apoptosis and angiogenesis, showed an increase in expression Inhibitors,Modulators,Libraries in the skin of 3 fold at 8 hours. Tnfrsf4, whose product has been implicated in promoting survival through induction of Bcl2 and BclXL expression in CD4 T cells, similarly showed an increase in expression of 2 fold at 8 hours. A pro angiogenic response in suprabasal epidermis The placental growth factor gene, Pgf? showed a marked increase from 8 hours throughout the time course for the skin. In contrast, a 2 fold down regulation was detected for the pancreas throughout much of the time course. Pgf is a member of the vascular endothelial growth factor family, and has been shown to result in increased numbers, branching and size of der mal blood vessels following over expression in basal ker atinocytes of adult mice. This may indicate a role in the development of neovasculature seen following MYC activation in the SBK.