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All rights reserved. http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI#_6 http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/version 1.4 http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI#_5 http://www.w3.org/ns/prov#value We chose to analyze pancreatic cancer cells since this tumor type displays the highest frequency of somatic mutations of RAS genes of all human malignancies (5, 22). Hs766T cells express activated KRAS and display elevated levels of pERK1/2 and pAKT (Fig. 4C). Treatment of Hs766T cells with the PI3'-kinase inhibitor LY294002 led to a selective decrease in pAKT with little or no effect on pERK1/2. By contrast, treatment of the cells with the MEK inhibitor U0126 or CI-1040 led to a selective decrease in pERK1/2 with little or no effect on pAKT. Strikingly, both the PI3'-kinase and the MEK inhibitors led to accumulation of p27Kip1 expression. These data are consistent with the observation that both MEK and PI3'-kinase inhibitors elicited a G0/G1 cell cycle arrest in Hs766T cells (data not shown). Further consistent with these observations, treatment of a panel of pancreatic cancer cells (eight cell lines) (57) with a MEK inhibitor (U0126 or CI-1040) led to a consistent G0/G1 cell cycle arrest accompanied by induced expression of p27Kip1 in all eight cell lines tested (S. Gysin and M. McMahon, sub- mitted for publication). For the most part, treatment of cells with MEK inhibitors led to a cytostatic rather than a cytotoxic effect, although cell death was often observed after prolonged treatment (+6 days). Treatment of pancreatic cancer cells with LY294002 led in some cases to a cytostatic effect and in others to a more rapid cytotoxic effect. Consistent with the observations in Fig. 4C, inhibition of PI3'-kinase by LY294002 led to elevated p27Kip1 expression in five of eight pancreas cancer cell lines tested. These data are fully consistent with the hypothesis that the RAS-activated RAF-MEK-ERK and PI3'-kinase- PDK-AKT pathways play a role in the regulation of p27Kip1 expression in bona fide human cancer cell lines. http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI#_5 http://www.w3.org/ns/prov#wasQuotedFrom http://www.ncbi.nlm.nih.gov/pubmed/15572689 http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI#_6 http://www.w3.org/2000/01/rdf-schema#label Selventa http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI#assertion http://www.w3.org/ns/prov#hadPrimarySource http://www.ncbi.nlm.nih.gov/pubmed/15572689 http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI#_5 http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI#pubinfo http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI http://purl.org/dc/terms/created 2014-07-03T14:30:29.950+02:00 http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI http://purl.org/pav/createdBy http://orcid.org/0000-0001-6818-334X http://www.tkuhn.ch/bel2nanopub/RAe6tU_U9c2R4vPpi4tc4SHn0JqPINe3bYiRq4ntktnrI http://purl.org/pav/createdBy http://orcid.org/0000-0002-1267-0234