ion, a mechanism which is thought to pre vent epidermal stem cells from becoming cancerous. One possible explanation for the contrasting behaviour in suprabasal epidermis, is that Ganetespib HSP (e.g. HSP90) SBKs are post mitotic and have already entered a terminal differentiation process. Subsequent activation of MYC in early SBK may promote loss of differentiation to enable cell cycle entry. Since MYC activated SBKs are already migrating upwards towards the skin surface, Inhibitors,Modulators,Libraries they are less likely to pose a cancer risk to the host given that they will ultimately be sloughed off as previously shown. We have previously shown that MYC activation in SBK results in a prominent angiogenic phenotype. From our microarray data, potential candidates that may promote such a response include Pgf, a member of the VEGF family, which was highly up regulated in skin but in fact down regulated in pancreas.
We also found Vegfa up regulated in skin but Inhibitors,Modulators,Libraries not in pancreas. Interest ingly Vegfc, which is important in growth of lymphatic vessels, was down regulated in skin but up regulated in pancreas. However, given that prominent angiogenesis is not detected in the skin until 3 4 days following MYC activation, it is possible that the short time course considered here is too early to identify a transcriptional response in all relevant genes relating to vascularisation. Kallikrein proteins have also been implicated in facilitat ing angiogenesis via degradation of the cellular matrix and our data showed co regulation of Pgf and Kal likrein genes.
These data suggest that the local tissue microenvironment in SBK that promote Inhibitors,Modulators,Libraries angiogenic growth may be linked to survival pathways that protect the cells against apoptosis. In summary, activation of MYC results in cell growth, loss of differentiation and Inhibitors,Modulators,Libraries cell cycle entry in both b cells and SBK in vivo. Apoptosis, which is confined to b cells, involves a combination of a DNA damage response and downstream activation of pro apoptotic signalling path ways, including Cdc2a and p19Arf p53, and downstream targets. Conversely, avoidance of apoptosis in SBK may result primarily from the activation of key anti apoptotic signalling pathways, particularly those Brefeldin_A involved in the Igf1 Akt pathway, and induction of an angiogenic response. A contributory role for intrinsic resistance to the induction of DNA damage and the p19Arf tumour suppressor pathway by MYC in SBK is also possible.
A possible mechanism whereby tis sue specific environmental factors may influence cell fate following MYC deregulation has also been pro posed, hypothesising that the decision to live or die may relate to the local tissue specific microenvironment. However, vitamin d this remains speculation as the approach taken here gives an insight into only one aspect of the changes occurring within the cell in response to MYC deregulation. Much remains to be learnt from analysis of protein level changes, post translational modifica tions, or epigenetic modifications of DNA. This study has identified several