title: Elimination of B-RAF in oncogenic C-RAF-expressing alveolar epithelial type II cells reduces MAPK signal intensity and lung tumor growth.
abstract: Tumors are often greatly dependent on signaling cascades promoting cell growth or survival and may become hypersensitive to inactivation of key components within these signaling pathways. Ras and RAF mutations found in human cancer confer constitutive activity to these signaling molecules thereby converting them into an oncogenic state. RAF dimerization is required for normal Ras-dependent RAF activation and is required for the oncogenic potential of mutant RAFs. Here we describe a new mouse model for lung tumor development to investigate the role of B-RAF in oncogenic C-RAF-mediated adenoma initiation and growth. Conditional elimination of B-RAF in C-RAF BxB-expressing embryonic alveolar epithelial type II cells did not block adenoma formation. However, loss of B-RAF led to significantly reduced tumor growth. The diminished tumor growth upon B-RAF inactivation was due to reduced cell proliferation in absence of senescence and increased apoptosis. Furthermore, B-RAF elimination inhibited C-RAF BxB-mediated activation of the mitogenic cascade. In line with these data, mutation of Ser-621 in C-RAF BxB abrogated in vitro the dimerization with B-RAF and blocked the ability to activate the MAPK cascade. Taken together these data indicate that B-RAF is an important factor in oncogenic C-RAF-mediated tumorigenesis.
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, 85152 Martinsried, Germany,. Electronic address: zanucco@biochem.mpg.de.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zanucco
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), 61231 Bad Nauheim, Germany, and.
authors.forename: Nefertiti
authors.initials: N
authors.lastname: El-Nikhely
authors.affiliation: Institute for Medical Radiation and Cell Research (MSZ), University of Würzburg, 97078 Würzburg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Götz
authors.affiliation: Institute for Medical Radiation and Cell Research (MSZ), University of Würzburg, 97078 Würzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Weidmann
authors.affiliation: Institute for Medical Radiation and Cell Research (MSZ), University of Würzburg, 97078 Würzburg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Pfeiffer
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), 61231 Bad Nauheim, Germany, and.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), 61231 Bad Nauheim, Germany, and.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, 85152 Martinsried, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, 85152 Martinsried, Germany,. Electronic address: Ulf.Rapp@mpi-bn.mpg.de.
authors.forename: Ulf R
authors.initials: UR
authors.lastname: Rapp
mesh_terms: D000236:Adenoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000201:enzymology* / Q000473:pathology; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000473:pathology
chemical_list: C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf
keywords: Cell Biology; Lung Cancer; Mitogen-activated Protein Kinase (MAPK); Mouse Genetics; Raf Kinase; Signal Transduction
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