Together, these results suggest that p8 is downstream of some cell growth regulators and therefore regulation of p8 expression or its activity could be used as a target for treating pancreatic cancer. Silencing p8 expression was able to strongly promote cell growth in both cell types, Panc selleck chem inhibitor 1 and BxPc 3, suggesting that p8 may act downstream of the ras or Smad4/DPC4 dependent ways. Also, we Inhibitors,Modulators,Libraries found that stimulating cell growth by the complex combination of growth factors contained in fetal calf serum down regulated expression of p8 whereas, on Inhibitors,Modulators,Libraries the contrary, treating the cells with TGF 1, which promotes cell cycle arrest, stimulates p8 expression. Therefore, p8 gene expression seems to be reg ulated in opposite directions by mechanisms promoting cell growth or cell cycle arrest.

It is interesting to note that while p8 expression is under Inhibitors,Modulators,Libraries the control of cell growth regulatory pathways such as Ras Raf MEK ERK, JNK, p38 and TGF Inhibitors,Modulators,Libraries 1, p8 can affect cell cycle progression, suggesting that p8 is a target for factors regulating pancre atic cell growth. A mechanism by which p8 could regulate cell cycle pro gression in embryonic fibroblasts was previously pro posed. In fact, p8 seems to take action upstream from cyclin dependent kinases because the intracellular levels and activities of Cdk2 and Cdk4 are decreased when p8 is expressed. Concomitantly, the cyclin dependent kinase inhibitor p27 is expressed at a low level in p8 deficient cells which may explain the increased activity of Cdk2 and Cdk4. The mechanism by which p8 regulates the intracel lular level of those proteins remains to be determined.

However, because p8 is a transcriptional cofactor, it is possible that regulation of expression of these molecules takes place, at least in part, at the transcription level. stress in fibroblasts but not in renal mesangial cells treated with endothelin. In pancreatic cancer derived cells p38 seems to play Inhibitors,Modulators,Libraries a major role since it is involved in p8 activation as judged by transient transfection assays and using a specific p38 inhibitor. In addition, p38 is also involved in TGF 1 induced p8 expression because about 40% of the TGF 1 effect was abolished http://www.selleckchem.com/products/MLN8237.html when p38 activity was specifically blocked. On the other hand, ERK and JNK are inducers of p8 expression in mesangial cells treated with endothelin, but not involved in the activation of p8 in response to stress in fibroblasts, and even repressors in pancreatic cells. Finally, PI3 kinase is an inducer of p8 expression in both endothelin mediated p8 activation in mesangial cells and pancreatic cells. Based on these observations, overexpression of p8 could be considered a possible goal for treating pancreatic tumours, in order to limit their growth.