ERK signalling and oncogene transformation are not impaired in cells lacking A-Raf

Mercer, Kathryn; Chiloeches, Antonio; Hüser, Martin; Kiernan, Michelle; Marais, Richard; Pritchard, Catrin

doi:10.1038/sj.onc.1205101

Cited by 58 publications

(52 citation statements)

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“…Mice containing knockout mutations of the raf-1 and Araf genes have been previously documented (Pritchard et al, 1996;Huser et al, 2001;Mercer et al, 2002). In contrast to the present study, the analysis of these single mutant mice provided no evidence for a role of A-Raf and Raf-1 in ERK1/2 activation or cell proliferation, but suggested an MEK kinase-independent role of Raf-1 in the prevention of apoptosis (Huser et al, 2001;Jesenberger et al, 2001;Mikula et al, 2001;Hindley and Kolch, 2002).…”

Section: Discussioncontrasting

confidence: 93%

“…However, the growth of the DKO MEFs was significantly compromised compared to MEFs of all other genotypes (Figure 3a). Apoptosis was induced by treatment of the primary MEFs with a-CD95 antibody and cell death was assessed by annexin V staining (Huser et al, 2001;Mercer et al, 2002). Treatment of cells with a-CD95 antibody led to a small but significant increase in apoptosis in all samples.…”

Section: Phenotype Analysis Of Single Knockout and Dko Micementioning

confidence: 99%

“…Despite the fact that single knockout mutations of either gene do not lead to noticeable changes in ERKl/2 activation (Huser et al, 2001;Mikula et al, 2001;Mercer et al, 2002), the combined knockout mutation of both genes leads to reduced ERKl/2 phosphorylation. These results indicate that A-Raf and Raf-1 play compensatory roles in ERKl/2 activation that cannot be rescued by B-Raf However, only transient ERK phosphorylation is significantly reduced in the double knockout (DKO) MEFs, whereas the sustained phase of ERK phosphorylation is not significantly affected.…”

Section: Introductionmentioning

confidence: 99%

“…In kinase cascade assays, immunoprecipitated B-Raf has a far stronger ability to activate MEK/ERK than Raf-1 and Raf-1, in turn, is far stronger than A-Raf (Huser et al, 2001). In B-raf À/À mouse embryonic fibroblasts (MEFs), ERK phosphorylation and activation are reduced to E30% that in wild-type cells (Wojnowski et al, 2000;Pritchard et al, 2004) whereas there is no noticeable decrease in ERK phosphorylation or activation in raf-1 À/À MEFs or A-raf À/Y MEFs (Huser et al, 2001;Mikula et al, 2001;Mercer et al, 2002). The ability of B-Raf to induce strong ERK activity has been highlighted by the discovery of activating mutations of the BRAF gene in human cancers (Davies et al, 2002;Kimura et al, 2003;Mercer and Pritchard, 2003).…”

Section: Introductionmentioning

confidence: 99%

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A-Raf and Raf-1 work together to influence transient ERK phosphorylation and Gl/S cell cycle progression

et al. 2005

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The Raf/MEK/ERK (extracellular regulated kinase) signal transduction pathway controls the ability of cells to respond to proliferative, apoptotic, migratory and differentiation signals. We have investigated the combined contribution of A-Raf and Raf-1 isotypes to signalling through this pathway by generating mice with knockout mutations of both A-raf and raf-1 genes. Double knockout (DKO) mice have a more severe phenotype than single null mutations of either gene, dying in embryogenesis at E10.5. The DKO embryos show no changes in apoptosis, but staining for Ki67 indicates a generalized reduction in proliferation. DKO mouse embryonic fibroblasts (MEFs) exhibit a delayed ability to enter S phase of the cell cycle. This is associated with a reduction in levels of transiently induced MEK and ERK phosphorylation and reduced expression of c-Fos and cyclin Dl. Levels of sustained ERK phosphorylation are not significantly altered. Thus, Raf-1 and A-Raf have a combined role in controlling physiological transient ERK activation and in maintenance of cell cycle progression at its usual rate.

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Section: Discussioncontrasting

confidence: 93%

Section: Phenotype Analysis Of Single Knockout and Dko Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A-Raf and Raf-1 work together to influence transient ERK phosphorylation and Gl/S cell cycle progression

et al. 2005

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“…These observations would place A-Raf in a NT-3-mediated neuronal survival pathway. The lack of A-Raf did not affect the regulation of ERK in mouse embryonic fibroblasts (MEFs) or the transformation of these cells, suggesting that these functions are compensated for by the other Raf family members (Mercer et al, 2002).…”

Section: Raf Gene Knockoutsmentioning

confidence: 99%

Conferring specificity on the ubiquitous Raf/MEK signalling pathway

2004

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The Raf-MEK-ERK signalling pathway controls fundamental cellular processes including proliferation, differentiation and survival. It remains enigmatic how this pathway can reliably convert a myriad of extracellular stimuli in specific biological responses. Recent results have shown that the Raf family isoforms A-Raf, B-Raf and Raf-1 have different physiological functions. Here we review how Raf isozyme diversity contributes to the specification of functional diversity, in particular regarding the role of Raf isozymes in cancer.

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Signalling by Ras and RhoGTPases

Wallace

Jaffe

2007

The Cancer Handbook

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RAS and RHO proteins constitute two branches of the RAS superfamily of small guanosine triphosphatases (GTPases) (Figure 1). Like all GTPases, these proteins cycle between an active, guanosine triphosphate (GTP)‐bound form, and an inactive, guanosine diphosphate (GDP)‐bound form. Two families of proteins, guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), activate and inactivate the GTPases, respectively, and the activity of GEFs and GAPs are controlled by a large number of cellular cues. Active GTPases interact with a diverse group of proteins, termed effectors , which transduce the signal from the GTPase, resulting in a range of cellular responses. RAS GTPases and components of the signalling pathways controlled by them are frequently mutated in human cancers. RHO GTPases are key regulators of many normal cellular processes which go awry during tumour progression.

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ERK signalling and oncogene transformation are not impaired in cells lacking A-Raf

Cited by 58 publications

References 19 publications

A-Raf and Raf-1 work together to influence transient ERK phosphorylation and Gl/S cell cycle progression

A-Raf and Raf-1 work together to influence transient ERK phosphorylation and Gl/S cell cycle progression

Conferring specificity on the ubiquitous Raf/MEK signalling pathway

Signalling by Ras and RhoGTPases

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