Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clar... more Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed gene...
Preservation of blood vessels integrity, which is critical for normal physiology and organ functi... more Preservation of blood vessels integrity, which is critical for normal physiology and organ function, is controlled at multiple levels, including endothelial junctions. However, the mechanism that controls the adequate assembly of endothelial cell junctions is not fully defined. Here we uncover TAp73 transcription factor as a vascular architect that orchestrates transcriptional programs involved in cell junction establishment and developmental blood vessel morphogenesis and identify Angiomotin (AMOT) as a TAp73 direct transcriptional target. Knockdown of p73 in endothelial cells not only results in decreased Angiomotin expression and localization at intercellular junctions, but also affects its downstream function regarding Yes-Associated Protein (YAP) cytoplasmic sequestration upon cell-cell contact. Analysis of adherens junctional morphology after p73-knockdown in human endothelial cells revealed striking alterations, particularly a sharp increase in serrated junctions and actin bu...
cell metabolism. Cells respond to decreased oxygen tension by inducing adaptive responses aimed a... more cell metabolism. Cells respond to decreased oxygen tension by inducing adaptive responses aimed at restoring oxygen availability and maintaining energy balance. Most responses to hypoxia are mediated by the activation of a family of transcription factors termed hypoxia-inducible factors (HIF). HIF have been shown to regulate vascular endothelial growth factor (VEGF) produced by hypoxic cells (such as those found in a rapidly-growing tumor mass) in an effort to increase local blood flow. As such, a role has been proposed for HIF in tumor-induced angiogenesis. Recently, the central molecular mechanism involved in the control of HIF activity by oxygen has been elucidated. Interestingly, an essential component of such a mechanism is the product of the tumor suppresser gene, vhl, and which suggests that HIF activation may contribute not only to tumor progression, but also to its genesis. In this review we discuss the involvement of HIF in the development and progression of human malignan...
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini r... more Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our
Resumen del poster presentado al XXXIX Congreso anual de la Sociedad Espanola de Bioquimica y Bio... more Resumen del poster presentado al XXXIX Congreso anual de la Sociedad Espanola de Bioquimica y Biologia Molecular, celebrado en Salamanca, del 5 al 8 de septiembre 2016.
Data extraction form in. This form includes all the information we intend to extract from the inc... more Data extraction form in. This form includes all the information we intend to extract from the included studies. (PDF 54Â kb)
Molecular gene signatures are useful tools to characterize the physiological state of cell popula... more Molecular gene signatures are useful tools to characterize the physiological state of cell populations, but most have developed under a narrow range of conditions and cell types and are often restricted to a set of gene identities.Focusing on the transcriptional response to hypoxia, we aimed to generate widely applicable classifiers sourced from the results of a meta-analysis of 69 differential expression datasets which included 425 individual RNA-seq experiments from 33 different human cell types exposed to different degrees of hypoxia (0.1-5%O2) for 2-48h.The resulting decision trees include both gene identities and quantitative boundaries, allowing for easy classification of individual samples without control or normoxic reference. Each tree is composed by 3-5 genes mostly drawn from a small set of just 8 genes (EGLN1, MIR210HG, NDRG1, ANKRD37, TCAF2, PFKFB3, BHLHE40, and MAFF). In spite of their simplicity, these classifiers achieve over 95% accuracy in cross validation and over...
Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are responsible for a hereditary c... more Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are responsible for a hereditary cancer syndrome characterized by high susceptibility to hemangioblastomas of the retina and central nervous system, pheochromocytomas, and renal cell carcinomas. In agreement with its role as a tumor suppressor, the vast majority of spontaneous clear cell carcinomas of the kidney present loss of heterozygosity at the VHL locus. Recently, it has been shown that VHL works as the substrate recognition component of an E3 ubiquitination complex that targets the hypoxia-inducible factor (HIF) for proteosomal degradation. Under normal oxygen tension, the half-life of HIF transcription factors is extremely short because of its high degradation rate by the proteasome, resulting in undetectable HIF activity in normal cells. However, in VHL-deficient tumor cells, the HIF transcriptional pathway is constitutively activated because of impaired ubiquitination of this transcription factor. To target VHL...
Low oxygen levels induce an adaptive response in cells through the activation of HIFs (hypoxia-in... more Low oxygen levels induce an adaptive response in cells through the activation of HIFs (hypoxia-inducible factors). These transcription factors are mainly regulated by a group of proline hydroxylases that, in the presence of oxygen, target HIF for degradation. The expression of two such enzymes, EGLN1 [EGL nine homologous protein 1, where EGL stands for egg laying defective (Caenorhabditis elegans gene)] and EGLN3, is induced by hypoxia through a negative feedback loop, and we have demonstrated recently that hypoxic induction of EGLN expression is HIF-dependent. In the present study, we have identified an HRE (hypoxia response element) in the region of the EGLN3 gene using a combination of bioinformatics and biological approaches. Initially, we isolated a number of HRE consensus sequences in a region of 40 kb around the human EGLN3 gene and studied their evolutionary conservation. Subsequently, we examined the functionality of the conserved HRE sequences in reporter and chromatin pre...
Hypoxia inducible factor (HIF) up-regulates the transcription of a few hundred genes required for... more Hypoxia inducible factor (HIF) up-regulates the transcription of a few hundred genes required for the adaptation to hypoxia. This restricted set of targets is in sharp contrast with the widespread distribution of the HIF binding motif throughout the genome. Here, we investigated the transcriptional response of GYS1 and RUVBL2 genes to hypoxia to understand the mechanisms that restrict HIF activity toward specific genes. GYS1 and RUVBL2 genes are encoded by opposite DNA strands and separated by a short intergenic region ($1 kb) that contains a functional hypoxia response element equidistant to both genes. However, hypoxia induced the expression of GYS1 gene only. Analysis of the transcriptional response of chimeric constructs derived from the intergenic region revealed an inhibitory sequence whose deletion allowed RUVBL2 induction by HIF. Enhancer blocking assays, performed in cell culture and transgenic zebrafish, confirmed the existence of an insulator element within this inhibitor...
Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clar... more Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed gene...
Preservation of blood vessels integrity, which is critical for normal physiology and organ functi... more Preservation of blood vessels integrity, which is critical for normal physiology and organ function, is controlled at multiple levels, including endothelial junctions. However, the mechanism that controls the adequate assembly of endothelial cell junctions is not fully defined. Here we uncover TAp73 transcription factor as a vascular architect that orchestrates transcriptional programs involved in cell junction establishment and developmental blood vessel morphogenesis and identify Angiomotin (AMOT) as a TAp73 direct transcriptional target. Knockdown of p73 in endothelial cells not only results in decreased Angiomotin expression and localization at intercellular junctions, but also affects its downstream function regarding Yes-Associated Protein (YAP) cytoplasmic sequestration upon cell-cell contact. Analysis of adherens junctional morphology after p73-knockdown in human endothelial cells revealed striking alterations, particularly a sharp increase in serrated junctions and actin bu...
cell metabolism. Cells respond to decreased oxygen tension by inducing adaptive responses aimed a... more cell metabolism. Cells respond to decreased oxygen tension by inducing adaptive responses aimed at restoring oxygen availability and maintaining energy balance. Most responses to hypoxia are mediated by the activation of a family of transcription factors termed hypoxia-inducible factors (HIF). HIF have been shown to regulate vascular endothelial growth factor (VEGF) produced by hypoxic cells (such as those found in a rapidly-growing tumor mass) in an effort to increase local blood flow. As such, a role has been proposed for HIF in tumor-induced angiogenesis. Recently, the central molecular mechanism involved in the control of HIF activity by oxygen has been elucidated. Interestingly, an essential component of such a mechanism is the product of the tumor suppresser gene, vhl, and which suggests that HIF activation may contribute not only to tumor progression, but also to its genesis. In this review we discuss the involvement of HIF in the development and progression of human malignan...
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini r... more Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our
Resumen del poster presentado al XXXIX Congreso anual de la Sociedad Espanola de Bioquimica y Bio... more Resumen del poster presentado al XXXIX Congreso anual de la Sociedad Espanola de Bioquimica y Biologia Molecular, celebrado en Salamanca, del 5 al 8 de septiembre 2016.
Data extraction form in. This form includes all the information we intend to extract from the inc... more Data extraction form in. This form includes all the information we intend to extract from the included studies. (PDF 54Â kb)
Molecular gene signatures are useful tools to characterize the physiological state of cell popula... more Molecular gene signatures are useful tools to characterize the physiological state of cell populations, but most have developed under a narrow range of conditions and cell types and are often restricted to a set of gene identities.Focusing on the transcriptional response to hypoxia, we aimed to generate widely applicable classifiers sourced from the results of a meta-analysis of 69 differential expression datasets which included 425 individual RNA-seq experiments from 33 different human cell types exposed to different degrees of hypoxia (0.1-5%O2) for 2-48h.The resulting decision trees include both gene identities and quantitative boundaries, allowing for easy classification of individual samples without control or normoxic reference. Each tree is composed by 3-5 genes mostly drawn from a small set of just 8 genes (EGLN1, MIR210HG, NDRG1, ANKRD37, TCAF2, PFKFB3, BHLHE40, and MAFF). In spite of their simplicity, these classifiers achieve over 95% accuracy in cross validation and over...
Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are responsible for a hereditary c... more Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are responsible for a hereditary cancer syndrome characterized by high susceptibility to hemangioblastomas of the retina and central nervous system, pheochromocytomas, and renal cell carcinomas. In agreement with its role as a tumor suppressor, the vast majority of spontaneous clear cell carcinomas of the kidney present loss of heterozygosity at the VHL locus. Recently, it has been shown that VHL works as the substrate recognition component of an E3 ubiquitination complex that targets the hypoxia-inducible factor (HIF) for proteosomal degradation. Under normal oxygen tension, the half-life of HIF transcription factors is extremely short because of its high degradation rate by the proteasome, resulting in undetectable HIF activity in normal cells. However, in VHL-deficient tumor cells, the HIF transcriptional pathway is constitutively activated because of impaired ubiquitination of this transcription factor. To target VHL...
Low oxygen levels induce an adaptive response in cells through the activation of HIFs (hypoxia-in... more Low oxygen levels induce an adaptive response in cells through the activation of HIFs (hypoxia-inducible factors). These transcription factors are mainly regulated by a group of proline hydroxylases that, in the presence of oxygen, target HIF for degradation. The expression of two such enzymes, EGLN1 [EGL nine homologous protein 1, where EGL stands for egg laying defective (Caenorhabditis elegans gene)] and EGLN3, is induced by hypoxia through a negative feedback loop, and we have demonstrated recently that hypoxic induction of EGLN expression is HIF-dependent. In the present study, we have identified an HRE (hypoxia response element) in the region of the EGLN3 gene using a combination of bioinformatics and biological approaches. Initially, we isolated a number of HRE consensus sequences in a region of 40 kb around the human EGLN3 gene and studied their evolutionary conservation. Subsequently, we examined the functionality of the conserved HRE sequences in reporter and chromatin pre...
Hypoxia inducible factor (HIF) up-regulates the transcription of a few hundred genes required for... more Hypoxia inducible factor (HIF) up-regulates the transcription of a few hundred genes required for the adaptation to hypoxia. This restricted set of targets is in sharp contrast with the widespread distribution of the HIF binding motif throughout the genome. Here, we investigated the transcriptional response of GYS1 and RUVBL2 genes to hypoxia to understand the mechanisms that restrict HIF activity toward specific genes. GYS1 and RUVBL2 genes are encoded by opposite DNA strands and separated by a short intergenic region ($1 kb) that contains a functional hypoxia response element equidistant to both genes. However, hypoxia induced the expression of GYS1 gene only. Analysis of the transcriptional response of chimeric constructs derived from the intergenic region revealed an inhibitory sequence whose deletion allowed RUVBL2 induction by HIF. Enhancer blocking assays, performed in cell culture and transgenic zebrafish, confirmed the existence of an insulator element within this inhibitor...
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Papers by Luis Del Peso