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



ID: 474531.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
RAF expression in human astrocytic tumors
Authors:Hagemann, C.; Gloger, J.; Anacker, J.; Said, H. M.; Gerngras, S.; Kuhnel, S.; Meyer, C.; Rapp, U. R.; Kammerer, U.; Vordermark, D.; Flentje, M.; Roosen, K.; Vince, G. H.
Date of Publication (YYYY-MM-DD):2009
Title of Journal:Int J Mol Med
Volume:23
Issue / Number:1
Start Page:17
End Page:31
Audience:Not Specified
Abstract / Description:RAF proteins are well known oncoproteins. The B-RAF has been shown to be activated by mutations in a multitude of human cancers. Alterations of C-RAF expression are discussed to play a role in lung cancer. Only for A-RAF no link to tumorigenesis has been published so far. Malignant gliomas are the most prevalent primary brain tumors of adults. They are highly invasive and very difficult to treat, despite of surgery, gamma-irradiation and chemotherapy. Although a role of the mitogenic Ras-RAF-MEK-ERK signalling cascade in brain tumor development is well established, there are only few reports available addressing alterations in RAF sequence or protein expression and function in human gliomas. We analysed the mutational status of A-RAF and B-RAF in human glioblastomas (GBM) by sequencing. Then we checked for RAF gene amplification by dot blot hybridization and examined RAF mRNA and protein expression patterns in human astrocytic gliomas of WHO grade II (LGA) and IV (GBM) by semiquantitative RT-PCR and Western blotting, respectively. The results were correlated with patients prognosis. Finally, we performed functional assays to address a putative function of A-RAF in glioma cell proliferation and migration. We showed that RAF mutations are a rare event in glioblastoma multiforme. A-raf gene amplification was more often detected and overexpression of all three RAF proteins on mRNA and protein level was regularly found in human malignant gliomas. Whereas A-RAF and C-RAF expression was negatively correlated with the patients prognosis, B-RAF expression had a positive effect. Since neither A-RAF, nor C-RAF expression had any influence on proliferation and migration of GBM cells, putative functions of C-RAF in angiogenesis and of A-RAF in regulation of metabolism are discussed. Our data indicate that RAF proteins might be valuable targets for small molecule therapies. However, initially specific functions of RAF during tumorigenesis have to be elucidated.
Free Keywords:Astrocytoma/diagnosis/*genetics/pathology; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation; Glioblastoma/diagnosis/*genetics/pathology; Humans; Mutant Proteins/genetics; Prognosis; Proto-Oncogene Proteins A-raf/chemistry/*genetics; Proto-Oncogene Proteins B-raf/chemistry/*genetics; Proto-Oncogene Proteins c-raf/chemistry/*genetics; RNA, Messenger/genetics; Sequence Analysis, DNA
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Department of Neurosurgery, Tumorbiology Laboratory, University of Wurzburg, D-97080 Wurzburg, Germany. hagemann_c@klinik.uni-wuerzburg.de
Identifiers:ISSN:1107-3756 (Print) 1107-3756 (Linking)
URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=..
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