Indeed, c Kit activation induces all of these pathways, while activated TrkA induces Ras Raf Erk, and PI3K pathways but does not cause tyrosine phosphorylation selleck chemicals of endogenous STATs, suggesting that SCF and NGF not only induce common signal path ways, but also induce unique signal pathways. However, the differences between a set of genes which are Inhibitors,Modulators,Libraries upregu lated by NGF and those upregulated by SCF in hemato poietic cells has not yet been studied. The rat pheochromocytoma cell line, PC12, is one of the most thoroughly established Inhibitors,Modulators,Libraries systems to study the NGF mediated signal transduction pathway followed by neuronal differentiation. Various studies have investi gated gene expression profiles Inhibitors,Modulators,Libraries in NGF treated PC12 cells, however whether these upregulated genes are similar to genes in the hematopoietic system is not clear.

Interestingly, leukemogenic mutant TrkA does not induce tumor formation, but induces the differentia tion of PC12 cells, suggesting that NGF TrkA signaling is different Inhibitors,Modulators,Libraries in neu ronal and hematopoietic cells. We have previously shown that NGF TrkA signaling partially rescues TrkA expressing Bcr Abl transformed chronic myelogenous leukemia cells, such as K562, and Meg 01, from cell death induced by a potent inhibitor of Bcr Abl tyro sine kinase, imatinib mesylate. However, the effects of NGF on imatinib treated CML cells are mod est. In the presence of NGF, the number of living K562 cells treated with imatinib increased by only 1. 5 fold within 4 days and Meg 01 cells did not grow, but just survived for a longer period.

A dramatic effect of NGF treatment was observed in oncogenic c Kit transformed human mastocytoma cells which are also induced to undergo apoptosis by treatment with imatinib. HMC 1 cells continue to grow nearly normally in the presence of both imatinib Inhibitors,Modulators,Libraries and NGF. In this paper, using HMC 1 cells we compared NGF and SCF signaling in the same cell sys tem. HMC 1 expresses the activated SCF receptor, V560G and or D816V c Kit and TrkA. The kinase activity of V560G c Kit can be inhibited com pletely by treatment with imatinib and cells died within 3 days. NGF rescues HMC 1 cells prolif eration, indicating that NGF can take over mitogenic signaling in these cells. Therefore, we compared the NGF mediated upregulated genes to the downregulated genes by imatinib treatment by transcriptome analy sis.

We found Kruppel like factor 2 and Smad family member 7 as the NGF mediated novel down stream genes in hematopoietic cells and KLF2 may be involved in NGF mediated survival selleck of imatinib treated cells. Results NGF rescues HMC 1 cells from imatinib mediated cell death and promotes proliferation To assess the biological effects of NGF on HMC 1 cells in the absence of c Kit mediated signal, we treated the cells with 5 uM imatinib in the presence or absence of 100 ng ml NGF. Viable cells were counted 1, 2, and 3 days after treatment using trypan blue cell exclusion assay.