Constitutive activation of raf-1 induces glioma formation in mice Journal Article
| Authors: | Lyustikman, Y.; Momota, H.; Pao, W.; Holland, E. C. |
| Article Title: | Constitutive activation of raf-1 induces glioma formation in mice |
| Abstract: | In human glioblastoma multiforme (GBM), RAS activity is upregulated in the majority of the tumors. Furthermore, the levels of phospho-mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK), a downstream effector of RAS, are also increased. In mice, activated KRas cooperates with the loss of INK4a-ARF locus or with activated Akt to induce gliomas, confirming an important role for this pathway in glioma biology. However, to correctly target therapies against the RAS signaling pathway, it is necessary to identify the effectors that contribute to RAS-mediated gliomagenesis. In this study, we investigated the contribution of RAF signaling in glioma oncogenesis. We find that the levels of RAF-1 and BRAF proteins and RAF kinase activity are increased in human GBM samples. We confirm the importance of this finding by demonstrating a causal role for a constitutively active Raf-1 mutant in glioma formation in mice. Specifically, we find that activated Raf-1 cooperates with Arf loss or Akt activation to generate gliomas similar to activated KRas under the same conditions. Our study suggests that the oncogenic effect of KRas in glioma formation may be transduced at least in part through Raf signaling and that therapeutic targeting of this pathway may be beneficial in glioma treatment. Copyright © 2008 Neoplasia Press, Inc. All rights reserved. |
| Keywords: | immunohistochemistry; controlled study; human tissue; mutation; raf protein; nonhuman; glioma; brain neoplasms; mouse; animals; mice; mice, knockout; animal tissue; animal experiment; enzyme activation; enzyme activity; carcinogenesis; immunoenzyme techniques; blotting, western; brain; glioblastoma; newborn; proto-oncogene proteins c-akt; cyclin-dependent kinase inhibitor p16; animals, newborn; genes, ras; b raf kinase; proto-oncogene proteins b-raf; proto-oncogene proteins c-raf |
| Journal Title: | NeoPlasia |
| Volume: | 10 |
| Issue: | 5 |
| ISSN: | 1522-8002 |
| Publisher: | Elsevier Science Inc. |
| Date Published: | 2008-05-01 |
| Start Page: | 501 |
| End Page: | 510 |
| Language: | English |
| DOI: | 10.1593/neo.08206 |
| PUBMED: | 18472967 |
| PROVIDER: | scopus |
| PMCID: | PMC2373912 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 21" - "Export Date: 17 November 2011" - "CODEN: NEOPF" - "Source: Scopus" |
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