Publications by authors named "Gloria Reyes"

16 Publications

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Ligation of newly replicated DNA controls the timing of DNA mismatch repair.

Curr Biol 2021 03 7;31(6):1268-1276.e6. Epub 2021 Jan 7.

DNA Repair Mechanisms and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Heidelberg 69120, Germany. Electronic address:

Mismatch repair (MMR) safeguards genome stability through recognition and excision of DNA replication errors. How eukaryotic MMR targets the newly replicated strand in vivo has not been established. MMR reactions reconstituted in vitro are directed to the strand containing a preexisting nick or gap, suggesting that strand discontinuities could act as discrimination signals. Another candidate is the proliferating cell nuclear antigen (PCNA) that is loaded at replication forks and is required for the activation of Mlh1-Pms1 endonuclease. Here, we discovered that overexpression of DNA ligase I (Cdc9) in Saccharomyces cerevisiae causes elevated mutation rates and increased chromatin-bound PCNA levels and accumulation of Pms1 foci that are MMR intermediates, suggesting that premature ligation of replication-associated nicks interferes with MMR. We showed that yeast Pms1 expression is mainly restricted to S phase, in agreement with the temporal coupling between MMR and DNA replication. Restricting Pms1 expression to the G2/M phase caused a mutator phenotype that was exacerbated in the absence of the exonuclease Exo1. This mutator phenotype was largely suppressed by increasing the lifetime of replication-associated DNA nicks, either by reducing or delaying Cdc9 ligase activity in vivo. Therefore, Cdc9 dictates a window of time for MMR determined by transient DNA nicks that direct the Mlh1-Pms1 in a strand-specific manner. Because DNA nicks occur on both newly synthesized leading and lagging strands, these results establish a general mechanism for targeting MMR to the newly synthesized DNA, thus preventing the accumulation of mutations that underlie the development of human cancer.
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http://dx.doi.org/10.1016/j.cub.2020.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281387PMC
March 2021

Identification of MLH2/hPMS1 dominant mutations that prevent DNA mismatch repair function.

Commun Biol 2020 12 10;3(1):751. Epub 2020 Dec 10.

DNA Repair Mechanisms and Cancer, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.

Inactivating mutations affecting key mismatch repair (MMR) components lead to microsatellite instability (MSI) and cancer. However, a number of patients with MSI-tumors do not present alterations in classical MMR genes. Here we discovered that specific missense mutations in the MutL homolog MLH2, which is dispensable for MMR, confer a dominant mutator phenotype in S. cerevisiae. MLH2 mutations elevated frameshift mutation rates, and caused accumulation of long-lasting nuclear MMR foci. Both aspects of this phenotype were suppressed by mutations predicted to prevent the binding of Mlh2 to DNA. Genetic analysis revealed that mlh2 dominant mutations interfere with both Exonuclease 1 (Exo1)-dependent and Exo1-independent MMR. Lastly, we demonstrate that a homolog mutation in human hPMS1 results in a dominant mutator phenotype. Our data support a model in which yeast Mlh1-Mlh2 or hMLH1-hPMS1 mutant complexes act as roadblocks on DNA preventing MMR, unraveling a novel mechanism that can account for MSI in human cancer.
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http://dx.doi.org/10.1038/s42003-020-01481-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730388PMC
December 2020

Inactivation of folylpolyglutamate synthetase Met7 results in genome instability driven by an increased dUTP/dTTP ratio.

Nucleic Acids Res 2020 01;48(1):264-277

DNA Repair Mechanisms and Cancer, German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany.

The accumulation of mutations is frequently associated with alterations in gene function leading to the onset of diseases, including cancer. Aiming to find novel genes that contribute to the stability of the genome, we screened the Saccharomyces cerevisiae deletion collection for increased mutator phenotypes. Among the identified genes, we discovered MET7, which encodes folylpolyglutamate synthetase (FPGS), an enzyme that facilitates several folate-dependent reactions including the synthesis of purines, thymidylate (dTMP) and DNA methylation. Here, we found that Met7-deficient strains show elevated mutation rates, but also increased levels of endogenous DNA damage resulting in gross chromosomal rearrangements (GCRs). Quantification of deoxyribonucleotide (dNTP) pools in cell extracts from met7Δ mutant revealed reductions in dTTP and dGTP that cause a constitutively active DNA damage checkpoint. In addition, we found that the absence of Met7 leads to dUTP accumulation, at levels that allowed its detection in yeast extracts for the first time. Consequently, a high dUTP/dTTP ratio promotes uracil incorporation into DNA, followed by futile repair cycles that compromise both mitochondrial and nuclear DNA integrity. In summary, this work highlights the importance of folate polyglutamylation in the maintenance of nucleotide homeostasis and genome stability.
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http://dx.doi.org/10.1093/nar/gkz1006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145683PMC
January 2020

A genetic screen pinpoints ribonucleotide reductase residues that sustain dNTP homeostasis and specifies a highly mutagenic type of dNTP imbalance.

Nucleic Acids Res 2019 01;47(1):237-252

DNA Repair Mechanisms and Cancer, German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany.

The balance and the overall concentration of intracellular deoxyribonucleoside triphosphates (dNTPs) are important determinants of faithful DNA replication. Despite the established fact that changes in dNTP pools negatively influence DNA replication fidelity, it is not clear why certain dNTP pool alterations are more mutagenic than others. As intracellular dNTP pools are mainly controlled by ribonucleotide reductase (RNR), and given the limited number of eukaryotic RNR mutations characterized so far, we screened for RNR1 mutations causing mutator phenotypes in Saccharomyces cerevisiae. We identified 24 rnr1 mutant alleles resulting in diverse mutator phenotypes linked in most cases to imbalanced dNTPs. Among the identified rnr1 alleles the strongest mutators presented a dNTP imbalance in which three out of the four dNTPs were elevated (dCTP, dTTP and dGTP), particularly if dGTP levels were highly increased. These rnr1 alleles caused growth defects/lethality in DNA replication fidelity-compromised backgrounds, and caused strong mutator phenotypes even in the presence of functional DNA polymerases and mismatch repair. In summary, this study pinpoints key residues that contribute to allosteric regulation of RNR's overall activity or substrate specificity. We propose a model that distinguishes between different dNTP pool alterations and provides a mechanistic explanation why certain dNTP imbalances are particularly detrimental.
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http://dx.doi.org/10.1093/nar/gky1154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326808PMC
January 2019

Alterations in cellular metabolism triggered by or inactivation cause imbalanced dNTP pools and increased mutagenesis.

Proc Natl Acad Sci U S A 2017 05 17;114(22):E4442-E4451. Epub 2017 Apr 17.

German Cancer Research Center, 69120 Heidelberg, Germany;

Eukaryotic DNA replication fidelity relies on the concerted action of DNA polymerase nucleotide selectivity, proofreading activity, and DNA mismatch repair (MMR). Nucleotide selectivity and proofreading are affected by the balance and concentration of deoxyribonucleotide (dNTP) pools, which are strictly regulated by ribonucleotide reductase (RNR). Mutations preventing DNA polymerase proofreading activity or MMR function cause mutator phenotypes and consequently increased cancer susceptibility. To identify genes not previously linked to high-fidelity DNA replication, we conducted a genome-wide screen in using DNA polymerase active-site mutants as a "sensitized mutator background." Among the genes identified in our screen, three metabolism-related genes (, , and ) have not been previously associated to the suppression of mutations. Loss of either the transcription factor Gln3 or inactivation of the CTP synthetase Ura7 both resulted in the activation of the DNA damage response and imbalanced dNTP pools. Importantly, these dNTP imbalances are strongly mutagenic in genetic backgrounds where DNA polymerase function or MMR activity is partially compromised. Previous reports have shown that dNTP pool imbalances can be caused by mutations altering the allosteric regulation of enzymes involved in dNTP biosynthesis (e.g., RNR or dCMP deaminase). Here, we provide evidence that mutations affecting genes involved in RNR substrate production can cause dNTP imbalances, which cannot be compensated by RNR or other enzymatic activities. Moreover, Gln3 inactivation links nutrient deprivation to increased mutagenesis. Our results suggest that similar genetic interactions could drive mutator phenotypes in cancer cells.
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http://dx.doi.org/10.1073/pnas.1618714114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465912PMC
May 2017

A Traditional Diet Is Associated with a Reduced Risk of Eczema and Wheeze in Colombian Children.

Nutrients 2015 Jun 25;7(7):5098-110. Epub 2015 Jun 25.

Respiratory Epidemiology and Public Health Group, National Heart & Lung Institute, Imperial College London, London SW3 6LR, UK.

Background: Diet might influence the risk of allergic diseases. Evidence from developing countries with high prevalence of childhood asthma is scant.

Methods: Information on wheeze, rhinitis, and eczema was collected from 3209 children aged 6-7 years in 2005, who were taking part in the International Study on Asthma and Allergy in Children (ISAAC) in Colombia. Intake frequency of twelve food groups was assessed. Associations between each food group and current wheeze, rhino-conjunctivitis, and eczema were investigated with multiple logistic regressions, adjusting for potential confounders. Simes' procedure was used to test for multiple comparisons.

Results: 14.9% of children reported wheeze in the last 12 months, 16% rhino-conjunctivitis, and 22% eczema. Eczema was negatively associated with consumption of fresh fruits and pulses three or more times per week (adjusted Odds ratio (aOR): 0.64; 95% Confidence Interval (CI): 0.49 to 0.83; p value = 0.004; and aOR: 0.62, 95% CI: 0.47 to 0.80; p value < 0.001, respectively). Current wheeze was negatively associated with intake of potatoes (aOR: 0.44, 95% CI: 0.31 to 0.62, p value = 0.005), whilst this outcome was positively associated with consumption of fast food (aOR: 1.76, 95% CI: 1.32 to 2.35, p value = 0.001). These associations remained statistically significant after controlling for multiple comparisons.

Conclusions: A traditional diet might have a protective effect against eczema and wheeze in Colombian children, whilst intake of fast foods increases this risk.
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http://dx.doi.org/10.3390/nu7075098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516989PMC
June 2015

New insights into the mechanism of DNA mismatch repair.

Chromosoma 2015 Dec 11;124(4):443-62. Epub 2015 Apr 11.

German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.

The genome of all organisms is constantly being challenged by endogenous and exogenous sources of DNA damage. Errors like base:base mismatches or small insertions and deletions, primarily introduced by DNA polymerases during DNA replication are repaired by an evolutionary conserved DNA mismatch repair (MMR) system. The MMR system, together with the DNA replication machinery, promote repair by an excision and resynthesis mechanism during or after DNA replication, increasing replication fidelity by up-to-three orders of magnitude. Consequently, inactivation of MMR genes results in elevated mutation rates that can lead to increased cancer susceptibility in humans. In this review, we summarize our current understanding of MMR with a focus on the different MMR protein complexes, their function and structure. We also discuss how recent findings have provided new insights in the spatio-temporal regulation and mechanism of MMR.
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http://dx.doi.org/10.1007/s00412-015-0514-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600670PMC
December 2015

Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output.

Proc Natl Acad Sci U S A 2014 Sep 8;111(38):E3957-65. Epub 2014 Sep 8.

Departments of Pharmacology and

Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) suppresses receptor tyrosine kinase (RTK) signaling output by a previously unidentified epigenetic mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for the protein kinase AKT, protein kinase C, and S6 kinase. Specifically, we show that nuclear-localized PHLPP suppresses histone phosphorylation and acetylation, in turn suppressing the transcription of diverse growth factor receptors, including the EGF receptor. These data uncover a much broader role for PHLPP in regulation of growth factor signaling beyond its direct inactivation of AKT: By suppressing RTK levels, PHLPP dampens the downstream signaling output of two major oncogenic pathways, the PI3 kinase/AKT and the Rat sarcoma (RAS)/ERK pathways. Our data are consistent with a model in which PHLPP modifies the histone code to control the transcription of RTKs.
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http://dx.doi.org/10.1073/pnas.1404221111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183331PMC
September 2014

MEK1 is required for PTEN membrane recruitment, AKT regulation, and the maintenance of peripheral tolerance.

Mol Cell 2013 Apr 28;50(1):43-55. Epub 2013 Feb 28.

Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.

The Raf/MEK/ERK and PI3K/Akt pathways are prominent effectors of oncogenic Ras. These pathways negatively regulate each other, but the mechanism involved is incompletely understood. We now identify MEK1 as an essential regulator of lipid/protein phosphatase PTEN, through which it controls phosphatidylinositol-3-phosphate accumulation and AKT signaling. MEK1 ablation stabilizes AKT activation and, in vivo, causes a lupus-like autoimmune disease and myeloproliferation. Mechanistically, MEK1 is necessary for PTEN membrane recruitment as part of a ternary complex containing the multidomain adaptor MAGI1. Complex formation is independent of MEK1 kinase activity but requires phosphorylation of T292 on MEK1 by activated ERK. Thus, inhibiting the ERK pathway reduces PTEN membrane recruitment, increasing phosphatidylinositol-3-phosphate accumulation and AKT activation. Our data offer a conceptual framework for the observation that activation of the PI3K pathway frequently mediate resistance to MEK inhibitors and for the promising results obtained by combined MEK/PI3K inhibition in preclinical cancer models.
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http://dx.doi.org/10.1016/j.molcel.2013.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625979PMC
April 2013

Mortality and risk factors for invasive fungal infections after the implementation of a fluconazole prophylaxis protocol in very low birth weight infants.

Bol Asoc Med P R 2013 ;105(4):9-13

Unlabelled: Fungal infections are a common cause of late-onset sepsis in very low birth weight infants and can impact mortality and morbidity. The purpose of this study is to determine the impact of systemic fluconazole prophylaxis in the prevalence of fungemia.

Methods: Subjects included 402 very low birth weight premature infants with birth weights between 500 and 1,250 grams admitted to the University Pediatric Hospital NICU over a six year period. The period before and after prophylaxis was retrospectively compared

Results: There was a marginal decrease in fungemia in the prophylaxis group (2.6% vs. 6.7%, p = 0.0525). Factors associated to fungemia were chorioamnionitis (p = 0.0240), H2-receptor inhibitors use (p = 0.0109), mechanical ventilati (p = 0.0049), prolonged antibiotic t py (p = 0.0015), and parenteral nutriti (p = 0.0048). Infants with fungemia had longer lengths of stay (p = 0.0143) and lower survival (p = 0.002).

Conclusion: Prophylaxis with fluconazole decreases mortality and morbidity in an environment with a high incidence of late onset fungal infections. Early identification and prevention of risk factors must be reinforced.
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November 2014

From pluripotency to islets: miRNAs as critical regulators of human cellular differentiation.

Adv Genet 2012 ;79:1-34

Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, USA.

MicroRNAs (miRNAs) actively regulate differentiation as pluripotent cells become cells of pancreatic endocrine lineage, including insulin-producing β cells. The process is dynamic; some miRNAs help maintain pluripotency, while others drive cell fate decisions. Here, we survey the current literature and describe the biological role of selected miRNAs in maintenance of both mouse and human embryonic stem cell (ESC) pluripotency. Subsequently, we review the increasing evidence that miRNAs act at selected points in differentiation to regulate decisions about early cell fate (definitive endoderm and mesoderm), formation of pancreatic precursor cells, endocrine cell function, as well as epithelial to mesenchymal transition.
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http://dx.doi.org/10.1016/B978-0-12-394395-8.00001-3DOI Listing
December 2012

Active site inhibitors protect protein kinase C from dephosphorylation and stabilize its mature form.

J Biol Chem 2011 Aug 29;286(33):28922-28930. Epub 2011 Jun 29.

Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0721. Electronic address:

Conformational changes acutely control protein kinase C (PKC). We have previously shown that the autoinhibitory pseudosubstrate must be removed from the active site in order for 1) PKC to be phosphorylated by its upstream kinase phosphoinositide-dependent kinase 1 (PDK-1), 2) the mature enzyme to bind and phosphorylate substrates, and 3) the mature enzyme to be dephosphorylated by phosphatases. Here we show an additional level of conformational control; binding of active site inhibitors locks PKC in a conformation in which the priming phosphorylation sites are resistant to dephosphorylation. Using homogeneously pure PKC, we show that the active site inhibitor Gö 6983 prevents the dephosphorylation by pure protein phosphatase 1 (PP1) or the hydrophobic motif phosphatase, pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP). Consistent with results using pure proteins, treatment of cells with the competitive inhibitors Gö 6983 or bisindolylmaleimide I, but not the uncompetitive inhibitor bisindolylmaleimide IV, prevents the dephosphorylation and down-regulation of PKC induced by phorbol esters. Pulse-chase analyses reveal that active site inhibitors do not affect the net rate of priming phosphorylations of PKC; rather, they inhibit the dephosphorylation triggered by phorbol esters. These data provide a molecular explanation for the recent studies showing that active site inhibitors stabilize the phosphorylation state of protein kinases B/Akt and C.
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http://dx.doi.org/10.1074/jbc.M111.272526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3190699PMC
August 2011

Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase C.

J Biol Chem 2009 May 26;284(22):15215-23. Epub 2009 Mar 26.

Department of Pharmacology and Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, California 92093-0721, USA.

PHLPP2 (PH domain leucine-rich repeat protein phosphatase 2) terminates Akt and protein kinase C (PKC) activity by specifically dephosphorylating these kinases at a key regulatory site, the hydrophobic motif (Ser-473 in Akt1). Here we identify a polymorphism that results in an amino acid change from a Leu to Ser at codon 1016 in the phosphatase domain of PHLPP2, which reduces phosphatase activity toward Akt both in vitro and in cells, in turn resulting in reduced apoptosis. Depletion of endogenous PHLPP2 variants in breast cancer cells revealed the Ser-1016 variant is less functional toward both Akt and PKC. In pair-matched high grade breast cancer samples we observed retention of only the Ser allele from heterozygous patients (identical results were observed in a pair-matched normal and tumor cell line). Thus, we have identified a functional polymorphism that impairs the activity of PHLPP2 and correlates with elevated Akt phosphorylation and increased PKC levels.
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http://dx.doi.org/10.1074/jbc.M901468200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2685702PMC
May 2009

A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal.

Nat Struct Mol Biol 2009 Mar 15;16(3):294-303. Epub 2009 Feb 15.

Max F. Perutz Laboratories, University of Vienna, Doktor-Bohr-Gasse 9, 1030 Vienna, Austria.

Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. Here we describe a previously uncharacterized, unexpected role of Mek1 in downregulating Mek2-dependent Erk signaling. Mek1 mediates the regulation of Mek2 in the context of a previously undiscovered Mek1-Mek2 complex. The Mek heterodimer is negatively regulated by Erk-mediated phosphorylation of Mek1 on Thr292, a residue missing in Mek2. Disabling this Erk-proximal negative-feedback step stabilizes the phosphorylation of both Mek2 and Erk in cultured cells and in vivo in Mek1 knockout embryos and mice. Thus, in disagreement with the current perception of the pathway, the role of Mek1 and Mek2 in growth factor-induced Erk phosphorylation is not interchangeable. Our data establish Mek1 as the crucial modulator of Mek and Erk signaling and have potential implications for the role of Mek1 and Mek2 in tumorigenesis.
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http://dx.doi.org/10.1038/nsmb.1564DOI Listing
March 2009

Comparison of postdischarge growth in adequate for gestational age and small for gestational age very low birthweight infants.

Ethn Dis 2008 ;18(2 Suppl 2):S2-118-22

Department of Pediatrics, Neonatology Section, University of Puerto Rico School of Medicine, San Juan, Puerto Rico, USA.

Introduction: Some small for gestational age (SGA) neonates have a higher weight gain rate than adequate for gestational age (AGA) neonates. The objectives of this study were to evaluate the postdischarge growth of a cohort of very low birthweight infants to determine the percentage of those born SGA that achieve catch-up growth and whether AGA infants maintain adequate growth.

Methods: We performed a record review at the high-risk follow-up clinics of a previously paired group of infants. The infant's weight, height, and head circumference percentile at their last clinic visit were determined by using sex-adjusted curves. We also documented if the patient had presented any type of delay.

Results: Of 216 infants that were included in the original cohort, only 116 had evidence of enrollment in the clinic. The percentage of SGA that achieved catch-up growth was 18.6% (n = 59). The percentage of adequate for gestational age that maintained adequate growth was 42.1% (n = 57). The rate of developmental delay was not different between the groups (44.0% vs 38.6%, P = .5).

Conclusions: We conclude that a high percentage of high-risk infants are developing postdischarge growth delay. This study demonstrates that both SGA infants as well as AGA infants present growth problems after discharge from the hospital, which emphasizes the importance of long-term followup.
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September 2008

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
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