The RAF proteins take centre stage. Nat. Rev

Institute of Cancer Research, Londinium, England, United Kingdom
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 12/2004; 5(11):875-85. DOI: 10.1038/nrm1498
Source: PubMed


Since their discovery over 20 years ago, the RAF proteins have been intensely studied. For most of that time, the focus of the field has been the C-RAF isoform and its role as an effector of the RAS proteins. However, a report that implicates B-RAF in human cancer has highlighted the importance of all members of this protein kinase family and recent studies have uncovered intriguing new data relating to their complex regulation and biological functions.

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    • "A major event in the neoplastic transformation of thyroid follicular cells is the constitutive activation of oncogenes: BRAF, RAS, or RET/PTC, a chromosomal rearrangement leading to the fusion between the 3 0 end of the RET receptor tyrosine kinase gene and a 5 0 fragment of various unrelated genes (Soares et al., 2004). These genetic alterations are associated with activation of the MEKeERK and/or the PI3K pathways, resulting in alteration of a variety of transcription factors that regulate cellular proliferation, differentiation and apoptosis Q3 (Ji et al., 2007; Nikiforov, 2002; Sobrinho-Sim~ oes et al., 2008; Wellbrock et al., 2004). "
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    ABSTRACT: Thyroid cancer (TC) is frequently associated with BRAF or RAS oncogenic mutations and RET/PTC rearrangements, with aberrant RAF-MEK-ERK and/or PI3K pathway activation. BRAF underlies ERK activation in most TC cells, but not in TPC-1 cells with RET/PTC1 rearrangement. Here, we show that depletion of RAF-1, a RAF family member with a poorly defined role in TC, decreases proliferation and increases apoptosis in TPC-1 cells and, less significantly, in cells harboring a BRAF(V600E) or HRAS(G13R) mutations, but without affecting ERK activation. We further demonstrate that constitutive activation of ERKs in TPC-1 cells is not caused by mutations in 50 oncogenes and tumor suppressors prone to activate the ERK pathway, or affected by inhibition of BRAF, MEK1/2 or PI3K. Our data indicate that RAF-1 is important for the survival of TPC-1 cells independently of the classical MEK1/2-ERK activation, offering new perspectives on RET/PTC signaling and for the therapy of thyroid cancers. Copyright © 2015. Published by Elsevier Ireland Ltd.
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    • "Du fait de cell), découvert à l'occasion d'un criblage cherchant à identifier des molécules létales vis-à-vis des cellules porteuses d'une mutation de l'oncogène HRas (HRas V12) [9]. L'érastine a donc été développée dans l'optique de traiter des cancers présentant une activation de la voie Ras-Raf-MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase), une des voies de transduction les plus importantes dans l'oncogenèse chez l'homme [10]. L'érastine induit la perte de viabilité des cellules cancéreuses sans les manifestations morphologiques ou biochimiques caractéristiques de l'apoptose (Figure 1) [11]. "
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    • "By contrast, LS mutants behaved as loss-of-function mutations of SHP2, impairing ERK activation [10] [11] [12]. Within the heart, ERK1/2 are activated at the plasma membrane by Raf-1, followed by activation of small G protein Ras [13]. Harris et al. showed that dominant negative Raf-1 inhibited ERK1/2 activation in transgenic mice, which were resistant to hypertrophic stress but developed significant cardiomyocyte apoptosis [14]. "
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