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Ras Pathway Activation in Malignant Mesothelioma

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Presentation on theme: "Ras Pathway Activation in Malignant Mesothelioma"— Presentation transcript:

1 Ras Pathway Activation in Malignant Mesothelioma
Manish R. Patel, DO, Blake A. Jacobson, PhD, Arpita De, Sandra P. Frizelle, MD, Pasi Janne, MD, Saritha C. Thumma, MD, Brian A. Whitson, MD, Faris Farassati, PhD, Robert A. Kratzke, MD  Journal of Thoracic Oncology  Volume 2, Issue 9, Pages (September 2007) DOI: /JTO.0b013e31811f3aab Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 Ras signaling activity in mesothelioma cells. (A) Ras-GTP (active form) pull-down assay. (B) extracellular-regulated kinase (ERK) 1/2 in vitro kinase activity assay detecting phosphorylation of Elk-1 fusion protein. (C) Akt in vitro kinase activity assay detecting phosphorylation of glucose synthase kinase-3 (GSK-3) fusion protein. (D) c-Jun N-terminal kinase (JNK) in vitro kinase activity assay detecting phosphorylation of c-Jun. (E) p38 mitogen-activated protein kinase (MAPK) in vitro kinase activity assay detecting phosphorylation of ATF-2 fusion protein. Journal of Thoracic Oncology 2007 2, DOI: ( /JTO.0b013e31811f3aab) Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 Inhibition of cell proliferation by blockade of Ras downstream effectors. (A, B) Cell proliferation after 48 and 96 hours of treatment with U0126 in H2596, H2373, and H2461 cell lines. (C, D) Cell proliferation after 48 and 72 hours of treatment with SP All proliferation assays were done in triplicate. Journal of Thoracic Oncology 2007 2, DOI: ( /JTO.0b013e31811f3aab) Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 U0126 and SP block the activity of extracellular-regulated kinase (ERK) 1/2 and c-Jun N-terminal (JNK), respectively. (A) ERK1/2 activity assay after treatment with 20 μM U0126. (B) JNK activity after treatment with 25 μM SP (C) Poly (ADP-ribose) polymerase (PARP) cleavage assay to assess for induction of apoptosis following treatment with inhibitors. C, vehicle; U, U0126; S, SP600125; G, gemcitabine. Journal of Thoracic Oncology 2007 2, DOI: ( /JTO.0b013e31811f3aab) Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

5 FIGURE 4 Evaluation of cap-dependent translation activation in mesothelioma. (A) Immunoblots in whole cell lysates for key proteins involved in cap-dependent translation. Isoforms of 4E-BP1 indicating progressive phosphorylation (inactivation) are indicated (α, β, γ). (B) In vitro cap-binding assay showing the relative amounts of (eukaryotic initiation factor 4E) eIF4E bound to 7mGTP-Sepharose beads in LP9 and mesothelioma cells. Results are expressed by densitometry and immunoblot as described in the text. Journal of Thoracic Oncology 2007 2, DOI: ( /JTO.0b013e31811f3aab) Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

6 FIGURE 5 Cap-dependent translation after treatment with Ras pathway inhibitors. (A) Immunoblot of 4E-BP1 showing the α (hypophosphorylated), β, and γ (hyperphosphorylated) isoforms before and after treatment with U0126 and SP (B) Cap-binding assay and vascular endothelial factor (VEGF) immunoblot after treatment with U0126 and SP C, vehicle (dimethyl sulfoxide); U, U0126; S, SP Journal of Thoracic Oncology 2007 2, DOI: ( /JTO.0b013e31811f3aab) Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

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