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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents



ID: 711837.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
Elimination of B-RAF in oncogenic C-RAF-expressing alveolar epithelial type II cells reduces MAPK signal intensity and lung tumor growth
Authors:Zanucco, E.; El-Nikhely, N.; Gotz, R.; Weidmann, K.; Pfeiffer, V.; Savai, R.; Seeger, W.; Ullrich, A.; Rapp, U. R.
Date of Publication (YYYY-MM-DD):2014-09-26
Title of Journal:J Biol Chem
Volume:289
Issue / Number:39
Start Page:26804
End Page:26816
Audience:Not Specified
Abstract / Description: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.
Free Keywords:Adenoma/*enzymology/genetics/pathology; Animals; Cell Transformation, Neoplastic/genetics/*metabolism/pathology; Epithelial Cells/*enzymology/pathology; Humans; Lung Neoplasms/*enzymology/genetics/pathology; *MAP Kinase Signaling System; Mice; Mice, Transgenic; Mutation; Proto-Oncogene Proteins B-raf/genetics/*metabolism; Proto-Oncogene Proteins c-raf/genetics/*metabolism; Pulmonary Alveoli/*enzymology/pathology; Respiratory Mucosa/*enzymology/pathology; Cell Biology; Lung Cancer; Mitogen-activated Protein Kinase (MAPK); Mouse Genetics; Raf Kinase; Signal Transduction
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:the 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. the Institute for Medical Radiation and Cell Research (MSZ), University of Wurzburg, 97078 Wurzburg, Germany. From the Department of Molecular Biology, Max Planck Institute of Biochemistry, 85152 Martinsried, Germany. From the Department of Molecular Biology, Max Planck Institute of Biochemistry, 85152 Martinsried, Germany, Ulf.Rapp@mpi-bn.mpg.de. %^ 1435822045
Identifiers:ISSN:1083-351X (Electronic) 0021-9258 (Linking) %R 10.1074/jbc.M114.558999
URL:http://www.ncbi.nlm.nih.gov/pubmed/25096573
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