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Počet príspevkov : 542 Registration date : 18.12.2013
| Predmet: In cases where the phosphorylated residue in the original phosphopeptide had le St február 12, 2014 7:54 am | |
| Although not all markers of sensitivity found for AML were also asso ciated with responses in lymphoma or multiple myeloma, we found that the phosphorylation signals of PML p S506 and MARCKS p S170 also positively correlate, with viability after treatment with PI 103 in our set of lym phoma AP24534 943319-70-8 and multiple myeloma cells, Similarly, phosphorylation signals on KRT25 p S7 and SKIV2L p T186 positively correlated with viability after treatment with JAK i while the phosphorylation of HNRNPU p 272 negative correlated with the viability after treatment with MEK i, Thus these data show that phos phorylation markers may be able to predict responses to kinase inhibitors across different diseases despite their marked differences in basal phosphorylation, Pathways and ontologies associated with responses to kinase inhibitors In order to investigate pathways represented in phos phopeptide sets associated with the responses of our AML cell line panel to kinase inhibitors, we performed a bioinformatics analysis using DAVID pathway analysis tools, This analysis was based on phosphopeptides correlating with responses with R 0.<br><br> 45 or R 0. 45. Phosphopeptides that correlated with the responses to MEK i and JAK i were present in proteins with diverse functions, including mRNA splicing, transcription and nuclear proteins.<br><br> PKC pathway members were AT-406 cell in vivo in vitro signifi cantly enriched in the dataset of phosphory lation sites that correlated with the resistance to PI 103, Ten phosphorylation sites on kinases, six of which are Ser Thr protein kinases, were also found to correlate with resistance, akt1 阻害剤 Phosphorylation sites on proteins involved in transcription were well repre sented in the dataset that correlated with sensitivity to PI 103 or with resistance, To assess whether phosphorylation sites on known members of PI3K, MEK, and JAK pathways would cor relate with the responses of our AML cell line panel to the kinase inhibitors tested, we also specifically consid ered phosphorylation sites that, based on the literature, are known to be downstream of these kinases.<br><br> Phos phorylation sites on 4EBP1 or Ribosomal S6, which are known to be downstream of PI3K mTOR, did not corre late with the responses of our cancer cell panel to the PI3K mTOR inhibitor PI 103, In contrast, it was interesting to observe that phosphorylation sites on two phosphopeptides derived from MARCKS, which are substrates of PKCs and which thus provide a measure of PKC activities, correlated with the resistance of our AML panel to PI 103, These results are in line with those from the pathway analysis shown in Additional file 10, Figure S6A suggesting a correlation between the phosphoryla tion of PKC pathway members and the resistance to PI 103 and raised the hypothesis that PI 103 resistant cells were using the PKC pathway to proliferate. To explore this possibility, we treated P31 Fuj, HEL, and MV4 11 cells with different combinations of the PI3K mTOR inhibitor PI 103 and the PKC inhibitor Go6976. | |
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