Instituto Leloir

Buenos Aires, Argentina

Instituto Leloir

Buenos Aires, Argentina
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Thomas M.G.,Instituto Leloir | Thomas M.G.,CONICET | Pascual M.L.,Instituto Leloir | Pascual M.L.,CONICET | And 8 more authors.
Cellular and Molecular Life Sciences | Year: 2014

The production of proteins from mRNAs localized at the synapse ultimately controls the strength of synaptic transmission, thereby affecting behavior and cognitive functions. The regulated transcription, processing, and transport of mRNAs provide dynamic control of the dendritic transcriptome, which includes thousands of messengers encoding multiple cellular functions. Translation is locally modulated by synaptic activity through a complex network of RNA-binding proteins (RBPs) and various types of non-coding RNAs (ncRNAs) including BC-RNAs, microRNAs, piwi-interacting RNAs, and small interference RNAs. The RBPs FMRP and CPEB play a well-established role in synaptic translation, and additional regulatory factors are emerging. The mRNA repressors Smaug, Nanos, and Pumilio define a novel pathway for local translational control that affects dendritic branching and spines in both flies and mammals. Recent findings support a role for processing bodies and related synaptic mRNA-silencing foci (SyAS-foci) in the modulation of synaptic plasticity and memory formation. The SyAS-foci respond to different stimuli with changes in their integrity thus enabling regulated mRNA release followed by translation. CPEB, Pumilio, TDP-43, and FUS/TLS form multimers through low-complexity regions related to prion domains or polyQ expansions. The oligomerization of these repressor RBPs is mechanistically linked to the aggregation of abnormal proteins commonly associated with neurodegeneration. Here, we summarize the current knowledge on how specificity in mRNA translation is achieved through the concerted action of multiple pathways that involve regulatory ncRNAs and RBPs, the modification of translation factors, and mRNA-silencing foci dynamics. © 2013 Springer Basel.


Perez-Perri J.I.,Instituto Leloir | Perez-Perri J.I.,CONICET | Acevedo J.M.,Instituto Leloir | Acevedo J.M.,CONICET | And 3 more authors.
International Journal of Molecular Sciences | Year: 2011

Reduction in oxygen levels below normal concentrations plays important roles in different normal and pathological conditions, such as development, tumorigenesis, chronic kidney disease and stroke. Organisms exposed to hypoxia trigger changes at both cellular and systemic levels to recover oxygen homeostasis. Most of these processes are mediated by Hypoxia Inducible Factors, HIFs, a family of transcription factors that directly induce the expression of several hundred genes in mammalian cells. Although different aspects of HIF regulation are well known, it is still unclear by which precise mechanism HIFs activate transcription of their target genes. Concomitantly, hypoxia provokes a dramatic decrease of general transcription that seems to rely in part on epigenetic changes through a poorly understood mechanism. In this review we discuss the current knowledge on chromatin changes involved in HIF dependent gene activation, as well as on other epigenetic changes, not necessarily linked to HIF that take place under hypoxic conditions. © 2011 by the authors.


Thomas M.G.,Instituto Leloir | Thomas M.G.,CONICET | Loschi M.,Instituto Leloir | Loschi M.,CONICET | And 4 more authors.
Cellular Signalling | Year: 2011

Processing bodies (PBs) and Stress Granules (SGs) are the founding members of a new class of RNA granules, known as mRNA silencing foci, as they harbour transcripts circumstantially excluded from the translationally active pool. PBs and SGs are able to release mRNAs thus allowing their translation. PBs are constitutive, but respond to stimuli that affect mRNA translation and decay, whereas SGs are specifically induced upon cellular stress, which triggers a global translational silencing by several pathways, including phosphorylation of the key translation initiation factor eIF2alpha, and tRNA cleavage among others. PBs and SGs with different compositions may coexist in a single cell. These macromolecular aggregates are highly conserved through evolution, from unicellular organisms to vertebrate neurons. Their dynamics is regulated by several signaling pathways, and depends on microfilaments and microtubules, and the cognate molecular motors myosin, dynein, and kinesin. SGs share features with aggresomes and related aggregates of unfolded proteins frequently present in neurodegenerative diseases, and may play a role in the pathology. Virus infections may induce or impair SG formation. Besides being important for mRNA regulation upon stress, SGs modulate the signaling balancing apoptosis and cell survival. Finally, the formation of Nuclear Stress Bodies (nSBs), which share components with SGs, and the assembly of additional cytosolic aggregates containing RNA -the UV granules and the Ire1 foci-, all of them induced by specific cell damage factors, contribute to cell survival. © 2010 Elsevier Inc.


De Lella Ezcurra A.L.,Instituto Leloir | Bertolin A.P.,Instituto Leloir | Melani M.,Instituto Leloir | Wappner P.,Instituto Leloir | Wappner P.,University of Buenos Aires
Developmental Dynamics | Year: 2012

Living organisms are constantly exposed to environmental and genetic perturbations. Biological robustness enables these organisms to maintain their functional stability in the presence of external or internal changes. It has been proposed that microRNAs (miRNAs), small non-coding regulatory RNAs, contribute to robustness of gene regulatory networks. The hypoxic response is a major and well-characterized example of a cellular and systemic response to environmental stress that needs to be robust. miRNAs regulate the response to hypoxia, both at the level of the main transcription factor that mediates this response, the hypoxia-inducible factor (HIF), and at the level of one of the most important systemic outcomes of the response: angiogenesis. In this review, we will take the hypoxic response as a paradigm of miRNAs participating in circuits that provide robustness to biological responses. © 2012 Wiley Periodicals, Inc.


Acevedo J.M.,Instituto Leloir | Acevedo J.M.,CONICET | Centanin L.,Instituto Leloir | Dekanty A.,Instituto Leloir | And 3 more authors.
PLoS ONE | Year: 2010

Background: The Hypoxia Inducible Factor (HIF) mediates cellular adaptations to low oxygen. Prolyl-4-hydroxylases are oxygen sensors that hydroxylate the HIF alpha-subunit, promoting its proteasomal degradation in normoxia. Three HIFprolyl hydroxylases, encoded by independent genes, PHD1, PHD2, and PHD3, occur in mammals. PHD2, the longest PHD isoform includes a MYND domain, whose biochemical function is unclear. PHD2 and PHD3 genes are induced in hypoxia to shut down HIF dependent transcription upon reoxygenation, while expression of PHD1 is oxygen-independent. The physiologic significance of the diversity of the PHD oxygen sensors is intriguing. Methodology and Principal Findings: We have analyzed the Drosophila PHD locus, fatiga, which encodes 3 isoforms, FgaA, FgaB and FgaC that are originated through a combination of alternative initiation of transcription and alternative splicing. FgaA includes a MYND domain and is homologous to PHD2, while FgaB and FgaC are shorter isoforms most similar to PHD3. Through a combination of genetic experiments in vivo and molecular analyses in cell culture, we show that fgaB but not fgaA is induced in hypoxia, in a Sima-dependent manner, through a HIF-Responsive Element localized in the first intron of fgaA. The regulatory capacity of FgaB is stronger than that of FgaA, as complete reversion of fga loss-of-function phenotypes is observed upon transgenic expression of the former, and only partial rescue occurs after expression of the latter. Conclusions and Significance: Diversity of PHD isoforms is a conserved feature in evolution. As in mammals, there are hypoxia-inducible and non-inducible Drosophila PHDs, and a fly isoform including a MYND domain co-exists with isoforms lacking this domain. Our results suggest that the isoform devoid of a MYND domain has stronger regulatory capacity than that including this domain.


Katz M.J.,Instituto Leloir | Gandara L.,Instituto Leloir | de Lella Ezcurra A.L.,Instituto Leloir | Wappner P.,Instituto Leloir | Wappner P.,University of Buenos Aires
Cellular and Molecular Life Sciences | Year: 2016

Regulation of protein synthesis contributes to maintenance of homeostasis and adaptation to environmental changes. mRNA translation is controlled at various levels including initiation, elongation and termination, through post-transcriptional/translational modifications of components of the protein synthesis machinery. Recently, protein and RNA hydroxylation have emerged as important enzymatic modifications of tRNAs, elongation and termination factors, as well as ribosomal proteins. These modifications enable a correct STOP codon recognition, ensuring translational fidelity. Recent studies are starting to show that STOP codon read-through is related to the ability of the cell to cope with different types of stress, such as oxidative and chemical insults, while correlations between defects in hydroxylation of protein synthesis components and STOP codon read-through are beginning to emerge. In this review we will discuss our current knowledge of protein synthesis regulation through hydroxylation of components of the translation machinery, with special focus on STOP codon recognition. We speculate on the possibility that programmed STOP codon read-through, modulated by hydroxylation of components of the protein synthesis machinery, is part of a concerted cellular response to stress. © 2016 Springer International Publishing


Pimentel J.,Instituto Leloir | Boccaccio G.L.,Instituto Leloir | Boccaccio G.L.,CONICET | Boccaccio G.L.,University of Buenos Aires
Frontiers in Molecular Neuroscience | Year: 2014

The transcriptome at the synapse consists of thousands of messengers encoding several cellular functions, including a significant number of receptors and ion channels and associated proteins. The concerted translational regulation of all these molecules contributes to the dynamic control of synaptic strength. Cumulative evidence supports that dendritic RNA granules and mRNA-silencingfoci play an important role in translational regulation. Several relevant RBPs - FMRP; FUS/TLS;TDP-43; Staufen; Smaug; Pumilio; CPEB; HuD; ZBP1; and DDX6 among others - form granules that contain dormant mRNAs repressed by multiple pathways. Recent reports indicate that dendritic granules may contain stalled polysomes, and furthermore, active translation may occur in association with RNA granules. Here, we discuss the molecules and pathways involved inthis continuum of RNA granules that contain masked mRNAs, mRNAs trapped in inactive polysomes or mRNAs engaged in translation. © 2014 Pimentel and Boccaccio.


PubMed | Howard Hughes Medical Institute, Instituto Leloir, Promega Corporation and Aurora University
Type: Journal Article | Journal: Cell reports | Year: 2016

Hypoxia-inducible factors (HIFs) are critical regulators of the cellular response to hypoxia. Despite theirestablished roles in normal physiology and numerous pathologies, the molecular mechanisms by which they control gene expression remain poorly understood. We report here a conserved role for the TIP60 complex as a HIF1 transcriptional cofactor in Drosophila and human cells. TIP60 (KAT5) is required for HIF1-dependent gene expression in fly cells and embryos and colorectal cancer cells. HIF1A interacts with and recruits TIP60 to chromatin. TIP60 is dispensable for HIF1A association with its target genes but is required for HIF1A-dependent chromatin modification and RNA polymerase II activation in hypoxia. In human cells, global analysis of HIF1A-dependent gene activity reveals that most HIF1A targets require either TIP60, the CDK8-Mediator complex, or both as coactivators for full expression in hypoxia. Thus, HIF1A employs functionally diverse cofactors to regulate different subsets of genes within its transcriptional program.


PubMed | Instituto Leloir, University of Buenos Aires, Niigata University and Keio University
Type: Journal Article | Journal: Nucleic acids research | Year: 2016

Adaptation to hypoxia depends on a conserved / heterodimeric transcription factor called Hypoxia Inducible Factor (HIF), whose -subunit is regulated by oxygen through different concurrent mechanisms. In this study, we have identified the RNA binding protein dMusashi, as a negative regulator of the fly HIF homologue Sima. Genetic interaction assays suggested that dMusashi participates of the HIF pathway, and molecular studies carried out in Drosophila cell cultures showed that dMusashi recognizes a Musashi Binding Element in the 3 UTR of the HIF transcript, thereby mediating its translational repression in normoxia. In hypoxic conditions dMusashi is downregulated, lifting HIF repression and contributing to trigger HIF-dependent gene expression. Analysis performed in mouse brains revealed that murine Msi1 protein physically interacts with HIF-1 transcript, suggesting that the regulation of HIF by Msi might be conserved in mammalian systems. Thus, Musashi is a novel regulator of HIF that inhibits responses to hypoxia specifically when oxygen is available.


PubMed | Instituto Leloir
Type: Journal Article | Journal: Cellular and molecular life sciences : CMLS | Year: 2016

Regulation of protein synthesis contributes to maintenance of homeostasis and adaptation to environmental changes. mRNA translation is controlled at various levels including initiation, elongation and termination, through post-transcriptional/translational modifications of components of the protein synthesis machinery. Recently, protein and RNA hydroxylation have emerged as important enzymatic modifications of tRNAs, elongation and termination factors, as well as ribosomal proteins. These modifications enable a correct STOP codon recognition, ensuring translational fidelity. Recent studies are starting to show that STOP codon read-through is related to the ability of the cell to cope with different types of stress, such as oxidative and chemical insults, while correlations between defects in hydroxylation of protein synthesis components and STOP codon read-through are beginning to emerge. In this review we will discuss our current knowledge of protein synthesis regulation through hydroxylation of components of the translation machinery, with special focus on STOP codon recognition. We speculate on the possibility that programmed STOP codon read-through, modulated by hydroxylation of components of the protein synthesis machinery, is part of a concerted cellular response to stress.

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