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Canuelo A.,University of Jaen | Martinez-Romero R.,University of Jaen | Martinez-Lara E.,University of Jaen | Sanchez-Alcazar J.A.,Andalusian Center for Developmental Biology | Siles E.,University of Jaen
Molecular and Cellular Biochemistry | Year: 2012

We previously reported that treatment with a single dose of deferoxamine (DFO), which acts as a hypoxic-mimetic agent, only induces reactive oxygen species (ROS) production in the presence of poly(ADP-ribose) polymerase (PARP-1). Given that mitochondria are one of the main sources of ROS, the present study was designed to assess the effect of DFO treatment on the activity of mitochondrial respiratory chain complexes, and more importantly, to determine whether this effect is modulated by PARP-1. We found that DFO treatment induced a progressive decline in complex II and IV activity, but that this activity was preserved in PARP-1 knock-out cells, demonstrating that this decrease is mediated by PARP-1. We also confirmed that complex II inhibition after DFO treatment occurs in parallel with poly-ADP ribosylation. Consequently, we recommend that PARP-1 activation be taken into account when using DFO as a hypoxia-mimetic agent, because it mediates alteration of the mitochondrial respiratory chain. © 2011 Springer Science+Business Media, LLC.


Gonzalez-Aguilera C.,The BRIC | Palladino F.,Ecole Normale Superieure de Lyon | Askjaer P.,Andalusian Center for Developmental Biology
Briefings in Functional Genomics | Year: 2014

The precise developmentalmap of the Caenorhabditis elegans cell lineage, as well as a complete genome sequence and feasibility of genetic manipulation make this nematode species highly attractive to study the role of epigenetics during development. Genetic dissection of phenotypical traits, such as formation of egg-laying organs or starvation-resistant dauer larvae, has illustrated how chromatin modifiers may regulate specific cell-fate decisions and behavioral programs. Moreover, the transparent body of C. elegans facilitates non-invasive microscopy to study tissue-specific accumulation of heterochromatin at the nuclear periphery.We also review here recent findings on how small RNA molecules contribute to epigenetic control of gene expression that can be propagated for several generations and eventually determine longevity. © The Author 2013. Published by Oxford University Press.


Eelderink-Chen Z.,Chromatin | Olmedo M.,Institute of Medical Psychology | Olmedo M.,Andalusian Center for Developmental Biology | Bosman J.,Groningen Research Institute of Pharmacy | Merrow M.,Institute of Medical Psychology
Methods in Enzymology | Year: 2015

Three properties are most often attributed to the circadian clock: a ca. 24-h free-running rhythm, temperature compensation of the circadian rhythm, and its entrainment to zeitgeber cycles. Relatively few experiments, however, are performed under entrainment conditions. Rather, most chronobiology protocols concern constant conditions. We have turned this paradigm around and used entrainment to study the circadian clock in organisms where a free-running rhythm is weak or lacking. We describe two examples therein: Caenorhabditis elegans and Saccharomyces cerevisiae. By probing the system with zeitgeber cycles that have various structures and amplitudes, we can demonstrate the establishment of systematic entrained phase angles in these organisms. We conclude that entrainment can be utilized to discover hitherto unknown circadian clocks and we discuss the implications of using entrainment more broadly, even in model systems that show robust free-running rhythms. © 2015 Elsevier Inc. All rights reserved.


Caldeira J.,University of Porto | Caldeira J.,Andalusian Center for Developmental Biology | Caldeira J.,Instituto Of Engineering Biomedica Ineb | Figueiredo J.,University of Porto | And 16 more authors.
Human Molecular Genetics | Year: 2015

Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. In gastric cancer, loss of Ecad expression is acommon event and is associated with disease aggressiveness and poor prognosis. However, the molecular mechanisms underlying the invasive process associated to Ecad dysfunction are far from understood. We hypothesized that deregulation of cell-matrix interactions could play an important role during this process. Thus, we focussed on LM-332, which is a major matrix component, and in Ecad/LM-332 crosstalk in the process of Ecaddependent invasion. To verify whethermatrix deregulationwas triggered by Ecad loss,we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. The relevance of this relationship was then confirmed in human primary tumours. In vivo, Ecad knockdown induced apoptosis; nonetheless, at the invasive front, cells ectopically expressed Laminin A and βPS integrin. In vitro, we demonstrated that, in two different gastric cancer cell models, Ecad-defective cells overexpressed Laminin γ2 (LM-γ2), β1 and β4 integrin, when compared with Ecadcompetent ones. We showed that LM-γ2 silencing impaired invasion and enhanced cell death, most likely via pSrc and pAkt reduction, and JNK activation. In human gastric carcinomas, we found a concomitant decrease in Ecad and increase in LM-γ2. This is the first evidence that ectopic Laminin expression depends on Ecad loss and allows Ecad-dysfunctional cells to survive and invade. This opens new avenues for using LM-γ2 signalling regulators as molecular targets to impair gastric cancer progression. © The Author 2015.


Pineiro C.,Andalusian Center for Developmental Biology | Pineiro C.,Max Planck Institute for Developmental Biology | Lopes C.S.,Andalusian Center for Developmental Biology | Lopes C.S.,University of Porto | Casares F.,Andalusian Center for Developmental Biology
Development (Cambridge) | Year: 2014

The visual system of insects is a multilayered structure composed externally by the compound eye and internally by the three ganglia of the optic lobe: Lamina, medulla and the lobula complex. The differentiation of lamina neurons depends heavily on Hedgehog (Hh) signaling, which is delivered by the incoming photoreceptor axons, and occurs in a wave-like fashion. Despite the primary role of lamina neurons in visual perception, it is still unclear how these neurons are specified from neuroepithelial (NE) progenitors. Here we show that a homothorax (hth)-eyes absent (eya)-sine oculis (so)- dachshund (dac) gene regulatory cassette is involved in this specification. Lamina neurons differentiate from NE progenitors that express hth, eya and so. One of the first events in the differentiation of lamina neurons is the upregulation of dac expression in response to Hh signaling. We show that this dac upregulation, which marks the transition from NE progenitors into lamina precursors, also requires Eya/So, the expression of which is locked in by mutual feedback. dac expression is crucial for lamina differentiation because it ensures repression of hth, a negative regulator of single-minded, and thus dac allows further lamina neuron differentiation. Therefore, the specification of lamina neurons is controlled by coupling the cell-autonomous hth-eya-so-dac regulatory cassette to Hh signaling. © 2014. Published by The Company of Biologists Ltd.

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