title: Lack of constitutive activation of MAP kinase pathway in human acute myeloid leukemia cells with N-Ras mutation.
abstract: Mitogen-activated protein (MAP) kinases act as transducers of extracellular signaling via tyrosine kinase-growth factor receptors and G-protein-linked receptors to transcription factors. Constitutive activation of MAP kinase has been observed in a variety of solid tumors including renal cancer and breast cancer. Recently, we have reported that constitutively activated MAP kinase was observed in 50% of human primary acute myeloid leukemia (AML) cells. Ras is one of the components of G-proteins and transduces the signal from cytokine receptors to raf-1 theoretically resulting in the activation of MAP kinase pathway. In the present study, we have examined the correlation of Ras mutations and the activation of MAP kinase pathway in patients with AML. Twenty out of 22 AML cases with activating N-Ras mutations showed no phosphorylated forms of ERK2. ERK2 phosphorylation was tightly correlated with ERK1 phosphorylation and MAP kinase activity detected by in vitro kinase assay. Three samples with N-Ras mutations were stimulated with IL-3, GM-CSF and G-CSF separately but ERK2 activation was induced in none of these samples stimulated with these cytokines. In contrast, ERK2 was constitutively activated in all of four pancreatic carcinoma cases with K-Ras mutation at codon 12. These results suggest that function of the Ras mutations may be different between solid tumors, such as pancreatic carcinoma and colorectal carcinoma, and AML. Mutated Ras does not always stimulate MAP kinase pathway constitutively and may rather inhibit classical MAP kinase cascade in AML blasts from leukemia patients.
authors.affiliation: First Department of Internal Medicine, Nagoya University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Iida
authors.forename: M
authors.initials: M
authors.lastname: Towatari
authors.forename: A
authors.initials: A
authors.lastname: Nakao
authors.forename: H
authors.initials: H
authors.lastname: Iida
authors.forename: H
authors.initials: H
authors.lastname: Kiyoi
authors.forename: Y
authors.initials: Y
authors.lastname: Nakano
authors.forename: M
authors.initials: M
authors.lastname: Tanimoto
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: T
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000208:Acute Disease; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D011905:Genes, ras; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D017354:Point Mutation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D016298:Hematopoietic Cell Growth Factors; D009363:Neoplasm Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins