Architecture of high mobility group protein I-C.DNA complex and its perturbation upon phosphorylation by Cdc2 kinase.

The 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-kappaB 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

Glioblastoma (GBM) is an extremely aggressive tumor of the central nervous system, with a prognosis of 12\u201315 months and just 3\u20135% 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\u2013mesenchymal 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

Balanço de massa e de energia do tratamento de drenagem ácida de mineração da Mina São Geraldo, Sideropolis, SC

Trabalho de Conclusão de Curso, apresentado para obtenção do grau de Bacharel, no Curso de Engenharia Ambiental da Universidade do Extremo Sul Catarinense, UNESC.A extração de carvão mineral durante anos foi executada de forma desordenada sem técnicas para minimizar os impactos e cuidar do meio ambiente. A ausência de legislações ambientais que atuasse para controlar essa atividade, fez com que inúmeras bocas de minas fossem abertas e abandonadas causando a geração da drenagem ácida de mina (DAM). Este efluente derivado da combinação de material sulfetado, água e oxigênio, é capaz de comprometer a qualidade dos recursos hídricos. Com o passar dos anos uma variedade de tecnologias foram desenvolvidas para evitar e/ou minimizar os impactos desta atividade e para garantir o cumprimento das legislações ambientais e o melhoramento da qualidade dos recursos hídricos da região. Uma dessas alternativas é o tratamento da drenagem ácida de mina. Estudos e pesquisas voltados a esta prática, resultaram no desenvolvimento de um sistema de tratamento de DAM em escala piloto com a utilização de ozônio e hidróxido de cálcio. Este estudo ampliou essa pesquisa testando outros neutralizantes como o hidróxido de sódio e o hidróxido de cálcio utilizados de forma individual e ainda combinados com o uso do ozônio. O hidróxido de cálcio e hidróxido de sódio foram utilizados de duas maneiras: na primeira, aplicados sem oxidante, sendo utilizados para precipitar os metais pesados e adequação dos valores de pH e, na segunda maneira aplicado-os após o uso do oxidante para a adequação dos valores de pH frente a legislação vigente e ocasionar a precipitação dos metais pesados. A utilização do oxidante ozônio muda a forma convencional de se fazer o tratamento nas Estações de Tratamento de Efluentes (ETEs) das mineradoras da região. Ainda, fez-se os cálculos no balanço de massa, balanço de energia e avaliação financeira para avaliar o custo-benefício dessas tecnologias. Fez-se uso do filtro prensa após os tratamentos para retenção dos sólidos e eliminação da parte líquida, assim como a quantificação desses dois componentes. Os resultados dos ensaios que demonstraram maior eficiência na remoção dos metais foram aqueles que utilizaram o ozônio. Em relação ao custo-benefício teve destaque a utilização do tratamento com hidróxido de cálcio e ozônio. Este projeto em planta piloto está em funcionamento no Setor Mina São Geraldo, no município de Siderópolis, pertencente à Empresa Rio Deserto

Issues to be Addressed for Transforming a Digital Library Application for Experts into One for Final Users

This paper reports on the effort we made in adapting and opening a specialist tool, focused on illumination and designed purposely for scholars and researchers, in order to be suitable also for the general public. We describe the ongoing process we are conducting: the adaptation and the improvement of the IPSA digital archive using the results we collected after several sessions of user interviews, following suggestions of both scholars and simple users. We discuss user studies dynamics, that we consider as a loop-interaction, and the consequences that they entail upon the system design.Department of Information Engineering, University of Padua, Via Gradenigo 6/a, 35131 Padua, Italy, Department of Cultural Heritage, University of Padua, Piazza Capitaniato 7, 35139 Padua, Italy

A novel HMGA1-CCNE2-YAP axis regulates breast cancer aggressiveness

High Mobility Group A1 (HMGA1) is an architectural chromatin factor that promotes neoplastic transformation and progression. However, the mechanism by which HMGA1 exerts its oncogenic function is not fully understood. Here, we show that cyclin E2 (CCNE2) acts downstream of HMGA1 to regulate the motility and invasiveness of basal-like breast cancer cells by promoting the nuclear localization and activity of YAP, the downstream mediator of the Hippo pathway. Mechanistically, the activity of MST1/2 and LATS1/2, the core kinases of the Hippo pathway, are required for the HMGA1- and CCNE2-mediated regulation of YAP localization. In breast cancer patients, high levels of HMGA1 and CCNE2 expression are associated with the YAP/TAZ signature, supporting this connection. Moreover, we provide evidence that CDK inhibitors induce the translocation of YAP from the nucleus to the cytoplasm, resulting in a decrease in its activity. These findings reveal an association between HMGA1 and the Hippo pathway that is relevant to stem cell biology, tissue homeostasis, and cancer

Editorial: Hormone Receptors and Breast Cancer

Breast cancer (BC) is the most commonly diagnosed cancer among women worldwide and one of the leading cause of cancer-related deaths. The majority of BCs arise from epithelial cells, either in the ducts or lobules, as the result of genetic and epigenetic alterations, which lead to aberrant growth control and disruption of intracellular signaling. Because of this, BC is considered a heterogeneous disease with multiple sub-types, with cells of distinct origin and function. In summary, these articles contribute to understanding the topic and gathering information about the molecular mechanisms that are involved in BC development and progression. A better knowledge of the mechanisms involved in the pathogenesis of BC could enable us to discovery new biomarkers for patient stratification and identify novel therapeutic targets

Transforming growth factor-β employs HMGA2 to elicit epithelial–mesenchymal transition

Epithelial–mesenchymal transition (EMT) occurs during embryogenesis, carcinoma invasiveness, and metastasis and can be elicited by transforming growth factor-β (TGF-β) signaling via intracellular Smad transducers. The molecular mechanisms that control the onset of EMT remain largely unexplored. Transcriptomic analysis revealed that the high mobility group A2 (HMGA2) gene is induced by the Smad pathway during EMT. Endogenous HMGA2 mediates EMT by TGF-β, whereas ectopic HMGA2 causes irreversible EMT characterized by severe E-cadherin suppression. HMGA2 provides transcriptional input for the expression control of four known regulators of EMT, the zinc-finger proteins Snail and Slug, the basic helix-loop-helix protein Twist, and inhibitor of differentiation 2. We delineate a pathway that links TGF-β signaling to the control of epithelial differentiation via HMGA2 and a cohort of major regulators of tumor invasiveness and metastasis. This network of signaling/transcription factors that work sequentially to establish EMT suggests that combinatorial detection of these proteins could serve as a new tool for EMT analysis in cancer patients

High Mobility Group I Proteins Interfere with the Homeodomains Binding to DNA

Homeodomains (HDs) constitute the DNA binding domain of several transcription factors that control cell differentiation and development in a wide variety of organisms. Most HDs recognize sequences that contain a 5'-TAAT-3' core motif. However, the DNA binding specificity of HD-containing proteins does not solely determine their biological effects, and other molecular mechanisms should be responsible for their ultimate functional activity. Interference by other factors in the HD/DNA interaction could be one of the processes by which HD-containing proteins achieve the functional complexity required for their effects on the expression of target genes. Using gel-retardation assay, we demonstrate that two members of the high mobility group I (HMGI) family of nuclear proteins (HMGI-C and HMGY) can bind to a subset of HD target sequences and inhibit HDs from binding to the same sequences. The inhibition of the HD/DNA interaction occurs while incubating HMGI-C with DNA either before or after the addition of the HD. The reduced half-life of the HD.DNA complex in the presence of HMGI-C, and the shift observed in the CD spectra recorded upon HMGI-C binding to DNA, strongly suggest that structural modifications of the DNA are responsible for the inhibition of the HD.DNA complex formation. Moreover, by co-transfection experiments we provide evidence that this inhibition can occur also in vivo. The data reported here would suggest that HMGI proteins may be potential regulators of the function of HD-containing proteins and that they are able to interfere with the access of the HD to their target genes

Mass spectrometric analysis of the HMGY protein from Lewis lung carcinoma. Identification of phosphorylation sites.

The primary structure of the Lewis lung carcinoma protein HMGY belonging to the nuclear group of proteins HMGI (high mobility group I) was determined using electrospray and fast atom bombardment mass spectrometry. It was demonstrated that the sequence of the tumor protein corresponds to the amino acid sequence derived from the cDNA from cultured cells and that the N-terminal serine residue is N-acetylated. Moreover, the two high performance liquid chromatography-purified forms Y1 and Y2 of the protein HMGY were shown to differ at the level of serine phosphorylation, since they contain three phosphate and two phosphate groups, respectively, in the C-terminal region. No other modification was detected in the remaining part of the molecule