Angel Nebreda - Academia.edu (original) (raw)

Papers by Angel Nebreda

Biochemical Journal, 2011

p38α mitogen-activated protein kinase (MAPK) is an ubiquitously expressed serine/threonine protei... more p38α mitogen-activated protein kinase (MAPK) is an ubiquitously expressed serine/threonine protein kinase, which is activated by many extracellular stimuli and coordinates numerous cellular processes . p38α can also negatively regulate malignant cell transformation, which seems to be accounted for by its inhibitory role on cell cycle progression and its stimulatory effect on apoptosis and differentiation .

Biochemical Journal

Exo-1,3-beta-D-glucanase secreted by Saccharomyces cerevisiae undergoes extracellular modificatio... more Exo-1,3-beta-D-glucanase secreted by Saccharomyces cerevisiae undergoes extracellular modifications in its carbohydrate moiety that change the affinity towards the lectin concanavalin A. The transition of negatively reacting enzyme form into positively reacting one depends on temperature. Results from experiments with glucono-delta-lactone and from treatments in vitro with hydrolases suggest a glycosidase-mediated mechanism.

Oncotarget, Jan 14, 2015

Colorectal cancer is a major health problem and the second cause of cancer related death in weste... more Colorectal cancer is a major health problem and the second cause of cancer related death in western countries. Signaling pathways that control tissue homeostasis are often deregulated during tumorigenesis and contribute to tumor development. Studies in mouse models have shown that the p38 MAPK pathway regulates homeostasis in colon epithelial cells but also plays an important role in colon tumor maintenance. In this study, we have investigated the role of p38 MAPK signaling in patient-derived xenografts (PDXs) from three different human colon tumors representing clinical heterogeneity and that recapitulate the human tumor conditions both at histological and molecular levels. We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tu...

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2015

Physical exercise is suggested for preventing or delaying senescence and Alzheimer&amp;am... more Physical exercise is suggested for preventing or delaying senescence and Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD). We have examined its therapeutic value in the advanced stage of AD-like pathology in 3xTg-AD female mice through voluntary wheel running from 12 to 15 months of age. Mice submitted to exercise showed improved body fitness, immunorejuvenation, improvement of behavior and cognition, and reduced amyloid and tau pathology. Brain tissue analysis of aged 3xTg-AD mice showed high levels of oxidative damage. However, this damage was decreased by physical exercise through regulation of redox homeostasis. Network analyses showed that oxidative stress was a central event, which correlated with AD-like pathology and the AD-related behaviors of anxiety, apathy, and cognitive loss. This study corroborates the importance of redox mechanisms in the neuroprotective effect of physical exercise, and supports the theory of the crucial role of oxidative stress in the switch from normal brain aging to pathological aging and AD.

Topics in Current Genetics, 2008

... (Perdiguero et al. 2007) T cells - Active MKK6 Mitotic arrest (↑ p53) (Pedraza-Alva et al. 20... more ... (Perdiguero et al. 2007) T cells - Active MKK6 Mitotic arrest (↑ p53) (Pedraza-Alva et al. 2006) ... 2002) HOSE - Oncogenic H-Ras Inhibition of prolif-eration (↑ p21Cip1) (Nicke et al. 2005) RIE-1 + Active MKK6 Inhibition of prolif-eration (↓ cyclin D1) (Pruitt et al. 2002) ...

Scientific Reports, 2013

INSERM U-1054, Université de Montpellier I et II. 29, rue de Navacelles 34090-Montpellier (France).

Nature Cell Biology, 2014

The mechanisms that allow colon cancer cells to form liver and lung metastases, and whether KRAS ... more The mechanisms that allow colon cancer cells to form liver and lung metastases, and whether KRAS mutation influences where and when metastasis occurs, are unknown. We provide clinical and molecular evidence showing that different MAPK signalling pathways are implicated in this process. Whereas ERK2 activation provides colon cancer cells with the ability to seed and colonize the liver, reduced p38 MAPK signalling endows cancer cells with the ability to form lung metastasis from previously established liver lesions. Downregulation of p38 MAPK signalling results in increased expression of the cytokine PTHLH, which contributes to colon cancer cell extravasation to the lung by inducing caspase-independent death in endothelial cells of the lung microvasculature. The concerted acquisition of metastatic traits in the colon cancer cells together with the sequential colonization of liver and lung highlights the importance of metastatic lesions as a platform for further dissemination.

Cell Cycle, 2014

Mitogen activated protein kinase (MAPK) signaling pathways convert extracellular signals into spe... more Mitogen activated protein kinase (MAPK) signaling pathways convert extracellular signals into specific cellular responses through a cascade of phosphorylation events. Hence, tight regulation of these signaling pathways is essential for normal cell function and deregulation leads to various diseases including tumorigenesis. Three major MAPK families have been found deregulated in cancer: ERK1 and ERK2 (ERK1/2), p38 MAPK and the Jun N-terminal kinase (JNK). In non-transformed cells, ERK1/2 are involved mainly in the mitogenesis response whereas p38 MAPK and JNK mediate cellular stress and inflammatory responses.

Trends in Cell Biology, 2006

The formation of skeletal muscle is a multistep process orchestrated by the basic helix-loop-heli... more The formation of skeletal muscle is a multistep process orchestrated by the basic helix-loop-helix myogenic regulatory factors (MRFs). A wide array of proteins can interact with the MRFs, resulting in either induction or repression of their myogenic potential and subsequent MRF-mediated muscle-specific transcription. Findings published over the past few years have unambiguously established a key role for the p38 MAP kinase pathway in the control of muscle gene expression at different stages of the myogenic process. Here, we discuss the mechanisms by which p38 MAP kinase controls skeletal muscle differentiation by regulating the sequential activation of MRFs and their transcriptional coactivators, including chromatin remodeling enzymes.

The EMBO Journal, 2004

Skeletal myogenesis is associated with the activation of four muscle regulatory factors (MRFs): M... more Skeletal myogenesis is associated with the activation of four muscle regulatory factors (MRFs): Myf5, MyoD, Myogenin and MRF4. Here we report that p38 mitogenactivated protein kinase represses the transcriptional activity of MRF4 (involved in late stages of myogenesis), resulting in downregulation of specific muscle genes. MRF4 is phosphorylated in vitro and in vivo by p38 on two serines (Ser31 and Ser42) located in the N-terminal transactivation domain, resulting in reduced MRF4-mediated transcriptional activity. In contrast, nonphosphorylatable MRF4 mutants display increased transcriptional activity and are able to advance both myoblast fusion and differentiation. We also show that expression of desmin and a-actin, but not muscle creatin kinase, decreased at late stages of muscle differentiation, correlating with the induction of MRF4 and p38 activation. Accordingly, inhibition of p38 during late myogenesis results in the upregulation of both desmin and a-actin. We propose that repression of MRF4 activity by p38 phosphorylation may represent a new mechanism for the silencing of specific muscle genes at the terminal stages of muscle differentiation. EMBO THE EMBO JOURNAL THE EMBO JOURNAL p38 MAPK decreases MRF4 transcriptional activity M Suelves et al &

RNA, 2009

Xenopus Vg1RBP is a member of the highly conserved IMP family of four KH-domain RNA binding prote... more Xenopus Vg1RBP is a member of the highly conserved IMP family of four KH-domain RNA binding proteins, with roles in RNA localization, translational control, RNA stability, and cell motility. Vg1RBP has been implicated in localizing Vg1 mRNAs to the vegetal cortex during oogenesis, in a process mediated by microtubules and microfilaments, and in migration of neural crest cells in embryos. Using c-mos morpholino, kinase inhibitors, and constitutely active recombinant kinases we show that Vg1RBP undergoes regulated phosphorylation by Erk2 MAPK during meiotic maturation, on a single residue, S402, located between the KH2 and KH3 domains. Phosphorylation temporally correlates with the release of Vg1 mRNA from its tight cortical association, assayed in lysates in physiological salt buffers, but does not affect RNA binding, nor self-association of Vg1RBP. U0126, a MAP kinase inhibitor, prevents Vg1RBP cortical release and Vg1 mRNA solubilization in meiotically maturing eggs, while injection of MKK6-DD, a constitutively activated MAP kinase kinase, promotes the release of both Vg1RBP and Vg1 mRNA from insoluble cortical structures. We propose that Erk2 MAP kinase phosphorylation of Vg1RBP regulates the protein:protein-mediated association of Vg1 mRNP with the cytoskeleton and/or ER. Since the MAP kinase site in Vg1RBP is conserved in several IMP homologs, this modification also has important implications for the regulation of IMP proteins in somatic cells.

$Research paper thumbnail of Proteomic analysis of p38α mitogen-activated protein kinase-regulated changes in membrane fractions of RAS-transformed fibroblasts$

PROTEOMICS, 2006

Oncogenic Ras signaling has been long known to play an important role in tumorigenesis and human ... more Oncogenic Ras signaling has been long known to play an important role in tumorigenesis and human cancer. In this report, we have used the sensitive 2-D-DIGE coupled to MS for the identification of proteins differentially expressed at the cell membrane level between oncogenic H-RasV12-transformed wild-type and p38a-deficient mouse embryo fibroblasts (MEFs). Following trifluoroethanol solubilization, 76 proteins were found to be differentially regulated. After PMF, 63 spots containing 42 different proteins were unequivocally identified by MALDI-TOF MS coupled with database interrogation. As expected, many of them were membrane proteins. Six proteins were selected for further validation studies based on their potential functional link with malignant transformation and signal transduction. These were prohibitin (PHB), protein disulfide isomerase 3 (PDIA3), focal adhesion kinase 2 (FAK2), c-GMP dependent protein kinase 2 (KGP2), NADH-ubiquinone oxidoreductase 30 kDa subunit (NUGM) and translationally controlled tumor protein (TCTP). All these proteins were up-regulated in the membranes of H-RasV12-transformed p38a-/-cells, except for prohibitin, which was down-regulated. An excellent correlation was found between DIGE results and Western blot studies, indicating the reliability of the 2-D-DIGE analysis. The available evidence about the putative function of the identified proteins supports the emerging role of p38a as a negative regulator of tumorigenesis. Further studies are in progress to elucidate the implications of these findings in the regulation of H-Rasinduced transformation by p38a signaling.

Oncogene, 2005

Proliferation of nontransformed cells is regulated by cellcell contacts, which are referred to as... more Proliferation of nontransformed cells is regulated by cellcell contacts, which are referred to as contact-inhibition. Despite its generally accepted importance for cell cycle control, knowledge about the intracellular signalling pathways involved in contact inhibition is scarce. In the present work we show that p38a mitogen-activated protein kinase (MAPK) is involved in the growth-inhibitory signalling cascade of contact inhibition in fibroblasts. p38a activity is increased in confluent cultures of human fibroblasts compared to proliferating cultures. Time course studies show a sustained activation of p38a in response to cell-cell contacts in contrast to a transient activation after serum stimulation. The induction of contact inhibition by addition of glutaraldehyde-fixed cells is impaired by pharmacological inhibition of p38 as well as in p38aÀ/À fibroblasts. Further evidence for a central role of p38a in contact inhibition comes from the observation that p38aÀ/À fibroblasts show a higher saturation density compared to wild-type (wt) fibroblasts, which is reversed by reconstituted expression of p38a. In agreement with a defect in contact inhibition, p27 Kip1 accumulation is impaired in p38aÀ/À fibroblasts compared to wt fibroblasts. Hence, our work shows a new role for p38a in contact inhibition and provides a mechanistic basis for the recently proposed tumour suppressive function of this MAPK pathway.

Nature Cell Biology, 2002

Par-1 kinase is critical for polarization of the Drosophila melanogaster oocyte and the one-cell ... more Par-1 kinase is critical for polarization of the Drosophila melanogaster oocyte and the one-cell Caenorhabditis elegans embryo. Although Par-1 localizes specifically to the posterior pole in both cells, neither its targets nor its function at the posterior pole have been elucidated. Here we show that Drosophila Par-1 phosphorylates the posterior determinant Oskar (Osk) and demonstrate genetically that Par-1 is required for accumulation of Osk protein. We show in cell-free extracts that Osk protein is intrinsically unstable and that it is stabilized after phosphorylation by Par-1. Our data indicate that posteriorly localized Par-1 regulates posterior patterning by stabilizing Osk. T he serine/threonine kinase Par-1 is required to establish anterior-posterior polarity in the one-cell C. elegans embryo and the Drosophila oocyte 1-3 . In addition to its involvement in axis formation, two other functions of Drosophila par-1 have been identified recently: maintenance of polarity in the follicular epithelium that covers the oocyte and maintenance of oocyte cell fate during the early stages of oogenesis 4,5 . Although the targets of Drosophila Par-1 are not known, the finding that the mammalian Par-1 homologue MARK regulates microtubule stability by phosphorylating microtubule-associated proteins 6 , raised the possibility that Par-1 regulates polarity by controlling microtubule dynamics. Par-1 may also function in posterior patterning and germ plasm assembly, as suggested by the specific localization of the kinase to the posterior pole of the one-cell C. elegans embryo and of the Drosophila oocyte 2-3 . Posterior patterning of the Drosophila embryo is regulated by the Osk protein, which accumulates at the posterior pole of the oocyte. Localized expression of Osk protein at the posterior pole is regulated at different steps. osk messenger RNA is transported to the posterior pole of the oocyte in a translationally repressed state. After correct localization, repression is relieved and osk mRNA is translated 7-11 . The accumulation of high levels of Osk protein at the posterior pole is critical for proper embryonic development, as Osk protein regulates patterning in a dose-dependent manner: low amounts of Osk are sufficient for abdomen formation, whereas high amounts of Osk are required for germ-cell specification 12,13 . Accumulation of high Osk protein levels is achieved by an autoregulatory mechanism. Osk regulates translation of its own mRNA by anchoring the osk mRNA at the posterior pole and enhancing its translation . The latter is presumably effected by Osk directly recruiting the translational activator Vasa (Vas) to the posterior pole . Therefore, Osk protein controls the positive feedback loop ensuring its own accumulation.

Nature Cell Biology, 2006

Here, we show that endogenous XRINGO protein accumulates transiently during meiosis I entry and t... more Here, we show that endogenous XRINGO protein accumulates transiently during meiosis I entry and then is downregulated. This tight regulation of XRINGO expression is the consequence of two interconnected mechanisms: processing and degradation. XRINGO processing involves recognition of at least three distinct phosphorylated recognition motifs by the SCF βTrCP ubiquitin ligase, followed by proteasome-mediated limited degradation, resulting in an amino-terminal XRINGO fragment. XRINGO processing is directly stimulated by several kinases, including protein kinase A and glycogen synthase kinase-3β, and may contribute to the maintenance of G2 arrest. On the other hand, XRINGO degradation after meiosis I is mediated by the ubiquitin ligase Siah-2, which probably requires phosphorylation of XRINGO on Ser 243 and may be important for the omission of S phase at the meiosis-I-meiosis-II transition in Xenopus oocytes.

Molecular Cell, 2008

Cell-cycle progression is regulated by cyclin-dependent kinases (CDKs). CDK1 and CDK2 can be also... more Cell-cycle progression is regulated by cyclin-dependent kinases (CDKs). CDK1 and CDK2 can be also activated by noncyclin proteins named RINGO/Speedy, which were identified as inducers of the G2/M transition in Xenopus oocytes. However, it is unclear how XRINGO triggers M phase entry in oocytes. We show here that XRINGO-activated CDKs can phosphorylate specific residues in the regulatory domain of Myt1, a Wee1 family kinase that plays a key role in the G2 arrest of oocytes. We have identified three Ser that are major phosphoacceptor sites for CDK/XRINGO but are poorly phosphorylated by CDK/cyclin. Phosphorylation of these Ser inhibits Myt1 activity, whereas their mutation makes Myt1 resistant to inhibition by CDK/XRINGO. Our results demonstrate that XRINGO-activated CDKs have different substrate specificity than the CDK/cyclin complexes. We also describe a mechanism of Myt1 regulation based on site-specific phosphorylation, which is likely to mediate the induction of G2/M transition in oocytes by XRINGO.