1,721,024 research outputs found
Architecture of high mobility group protein I-C center dot DNA complex and its perturbation upon phosphorylation by Cdc2 kinase
No full textThe high mobility group I-C (HMGI-C) protein is an abundant component of rapidly proliferating undifferentiated cells. High level expression of this protein is characteristic for early embryonic tissue and diverse tumors. HMGI-C can function as an architectural factor enhancing the activity of transcription factor NF-kappa B on the beta-interferon promoter. The protein has three minor groove DNA-binding domains (AT-hooks), Here, we describe the complex of HMGI-C with a fragment of the beta-interferon promoter, We show that the protein binds to NRDI and PRDII elements of the promoter with its first and second AT-hook, respectively. Phosphorylation by Cdc2 kinase leads to a partial derailing of the AT-hooks from the minor groove, affecting mainly the second binding domain. In contrast, binding to long AT stretches of DNA involves contacts with all three AT-hooks and is marginally sensitive to phosphorylation, Our data stress the importance of conformation of the DNA binding site and protein phosphorylation for its function
Proneural-Mesenchymal Transition: Phenotypic Plasticity to Acquire Multitherapy Resistance in Glioblastoma
Full text linkGlioblastoma (GBM) is an extremely aggressive tumor of the central nervous system, with a prognosis of 12–15 months and just 3–5% of survival over 5 years. This is mainly because most patients suffer recurrence after treatment that currently consists in maximal resection followed by radio- and chemotherapy with temozolomide. The recurrent tumor shows a more aggressive behavior due to a phenotypic shift toward the mesenchymal subtype. Proneural-mesenchymal transition (PMT) may represent for GBM the equivalent of epithelial–mesenchymal transition associated with other aggressive cancers. In this review we frame this process in the high degree of phenotypic inter- and intra-tumor heterogeneity of GBM, which exists in different subtypes, each one characterized by further phenotypic variability in its stem-cell compartment. Under the selective pressure of different treatment agents PMT is induced. The mechanisms involved, as well as the significance of such event in the acquisition of a multitherapy resistance phenotype, are taken in consideration for future perspectives in new anti-GBM therapeutic options
Xenopus HMGA2 is required for neural crest cell survival and migration
No full textHMGA proteins are chromatin “architectural modifiers”, bearing three conserved “AT-hook” DNA binding motifs though which they assist in regulation of gene transcription. We have cloned Xenopus laevis hmga2β (Xhmga2β) and studied its developmental expression. By in situ hybridisation (ISH), localized transcripts are first detected at neurula stages, in the presumptive central nervous system (CNS) and eye field, and in the neural crest cell (NCC) presumptive territory. At tailbud and tadpole stages, Xhmga2β mRNA is detected in the CNS, in the otic vesicles, in migrating neural crest cell and their derivatives, in the notochord and in the medio-lateral mesoderm. In order to address the functional roles of Xhmga2β in the neural derivatives, we have injected morpholinos against Xhmga2β in a loss-of-function approach, targeting the morpholino to the dorsal region. Injected embryos typically show very strong abnormalities in the branchial region, where the branchial arches are lost or severely disrupted. Analysis of NCC molecular markers show severe downregulation or absence of Xtwist, and Xdll4 expression at the tailbud stage. TUNEL staining on injected embryos shows that extensive cell death occurs in the regions normally occupied by NCC. Injection of control morpholinos did not lead to similar alterations. The effects of the morpholino injection are rescued by coinjection of a synthetic Xhmga2β mRNA that is not targeted by the morpholino. These data suggest that Xhmga2β is required for NCC survival, possibly during the stage when NCC migrate in the visceral arches
The Epithelial–Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression
Full text linkThe transition between epithelial and mesenchymal phenotype is emerging as a key determinant of tumor cell invasion and metastasis. It is a plastic process in which epithelial cells first acquire the ability to invade the extracellular matrix and migrate into the bloodstream via transdiffer-entiation into mesenchymal cells, a phenomenon known as epithelial–mesenchymal transition (EMT), and then reacquire the epithelial phenotype, the reverse process called mesenchymal–epithelial transition (MET), to colonize a new organ. During all metastatic stages, metabolic changes, which give cancer cells the ability to adapt to increased energy demand and to withstand a hostile new environment, are also important determinants of successful cancer progression. In this review, we describe the complex interaction between EMT and metabolism during tumor progression. First, we outline the main connections between the two processes, with particular emphasis on the role of cancer stem cells and LncRNAs. Then, we focus on some specific cancers, such as breast, lung, and thyroid cancer
INHIBITION OF T7 RNA POLYMERASE TRANSCRIPTION BY PHOSPHATE AND PHOSPHOROTHIOATE TRIPLEX-FORMING OLIGONUCLEOTIDES TARGETED TO A R•Y SITE DOWNSTREAM FORM THE PROMOTER
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Gene network analysis using SWIM reveals interplay between the transcription factor‐encoding genes HMGA1, FOXM1, and MYBL2 in triple‐negative breast cancer
No full textAmong breast cancer subtypes, triple-negative breast cancer (TNBC) is the most aggressive with the worst prognosis and the highest rates of metastatic disease. To identify TNBC gene signatures, we applied the network-based methodology implemented by the SWIM software to gene expression data of TNBC patients in The Cancer Genome Atlas (TCGA) database. SWIM enables to predict key (switch) genes within the co-expression network, whose perturbations in expression pattern and abundance may contribute to the (patho)biological phenotype. Here, SWIM analysis revealed an interesting interplay between the genes encoding the transcription factors HMGA1, FOXM1, and MYBL2, suggesting a potential cooperation among these three switch genes in TNBC development. The correlative nature of this interplay in TNBC was assessed by in vitro experiments, demonstrating how they may actually modulate the expression of each other
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
HMGA2 Antisense Long Non-coding RNAs as New Players in the Regulation of HMGA2 Expression and Pancreatic Cancer Promotion
Full text linkNatural antisense long non-coding RNAs (lncRNAs) are regulatory RNAs transcribed from the opposite strand of either protein coding or non-coding genes, able to modulate their own sense gene expression. Hence, their dysregulation can lead to pathologic processes. Cancer is a complex class of diseases determined by the aberrant expression of a variety of factors, among them, the oncofetal chromatin architectural proteins High Mobility Group A (HMGA) modulate several cancer hallmarks. Thus, we decided to investigate the presence of natural antisense lncRNAs in HMGA1 and HMGA2 loci, and their possible involvement in gene expression regulation. Our results describe novel antisense lncRNAs associated with HMGA1 and HMGA2 genes. In particular, we demonstrate that HMGA2-AS1 is involved in the regulation of its own sense gene expression, mediating tumorigenesis. Thus, we highlight a new layer of complexity in the regulation of HMGA2 expression, providing new potential targets for cancer therapy
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