Publications by authors named "Dana Matzen"

3 Publications

  • Page 1 of 1

Essential role of B-Raf in oligodendrocyte maturation and myelination during postnatal central nervous system development.

J Cell Biol 2008 Mar;180(5):947-55

Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.

Mutations in the extracellular signal-regulated kinase (ERK) pathway, particularly in the mitogen-activated protein kinase/ERK kinase (MEK) activator B-Raf, are associated with human tumorigenesis and genetic disorders. Hence, B-Raf is a prime target for molecule-based therapies, and understanding its essential biological functions is crucial for their success. B-Raf is expressed preferentially in cells of neuronal origin. Here, we show that in mice, conditional ablation of B-Raf in neuronal precursors leads to severe dysmyelination, defective oligodendrocyte differentiation, and reduced ERK activation in brain. Both B-Raf ablation and chemical inhibition of MEK impair oligodendrocyte differentiation in vitro. In glial cell cultures, we find B-Raf in a complex with MEK, Raf-1, and kinase suppressor of Ras. In B-Raf-deficient cells, more Raf-1 is recruited to MEK, yet MEK/ERK phosphorylation is impaired. These data define B-Raf as the rate-limiting MEK/ERK activator in oligodendrocyte differentiation and myelination and have implications for the design and use of Raf inhibitors.
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http://dx.doi.org/10.1083/jcb.200709069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265404PMC
March 2008

ERK and beyond: insights from B-Raf and Raf-1 conditional knockouts.

Cell Cycle 2006 Jul 17;5(14):1514-8. Epub 2006 Jul 17.

Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.

The Raf/MEK/ERK cascade is a highly conserved signal transduction module whose activation reportedly results in a plethora of physiological outcomes. Depending on the cell type or the stimulus used, the pathway has been implicated in proliferation, differentiation, survival, and migration. Their wide range of activities renders the component of the Raf/MEK/ERK pathway prime candidates for molecule-targeted therapies, in particular, but not exclusively, in the context of cancer. Ras, Raf and MEK inhibitors have been developed, and some of them are in advanced clinical trials. Somewhat surprising in view of all this interest, our understanding of the fundamental biology of the ERK pathway in vivo is still scanty. Its investigation has been hampered by the fact that conventional targeting of many of these genes results in embryonic lethality. Recently, we and others have generated mouse strains that allow the conditional ablation of the genes coding for Raf-1, B-Raf and MEK-1. We are using these tools to identify the essential biological functions of these kinases, and to understand how the ERK pathway is wired in vivo. Here, we discuss some of the surprises yielded by the analysis of the role of B-Raf and Raf-1 and of their downstream effectors.
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http://dx.doi.org/10.4161/cc.5.14.2981DOI Listing
July 2006

Essential role of B-Raf in ERK activation during extraembryonic development.

Proc Natl Acad Sci U S A 2006 Jan 23;103(5):1325-30. Epub 2006 Jan 23.

Max F. Perutz Laboratories, Vienna Biocenter, Dr. Bohr Gasse 9, 1030 Vienna, Austria.

The kinases of the Raf family have been intensively studied as activators of the mitogen-activated protein kinase kinase/extra-cellular signal-regulated kinase (ERK) module in regulated and deregulated proliferation. Genetic evidence that Raf is required for ERK activation in vivo has been obtained in lower organisms, which express only one Raf kinase, but was hitherto lacking in mammals, which express more than one Raf kinase. Ablation of the two best studied Raf kinases, B-Raf and Raf-1, is lethal at midgestation in mice, hampering the detailed study of the essential functions of these proteins. Here, we have combined conventional and conditional gene ablation to show that B-Raf is essential for ERK activation and for vascular development in the placenta. B-Raf-deficient placentae show complete absence of phosphorylated ERK and strongly reduced HIF-1alpha and VEGF levels, whereas all these parameters are normal in Raf-1-deficient placentae. In addition, neither ERK phosphorylation nor development are affected in B-raf-deficient embryos that are born alive obtained by epiblast-restricted gene inactivation. The data demonstrate that B-Raf plays a nonredundant role in ERK activation during extraembyronic mammalian development in vivo.
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http://dx.doi.org/10.1073/pnas.0507399103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1360532PMC
January 2006
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