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Yokotsuka M.,Tokyo Medical University | Iwaya K.,Tokyo Medical University | Iwaya K.,National Defense Medical College | Saito T.,Juntendo University | And 5 more authors.
Breast Cancer Research and Treatment | Year: 2011

The final signal for triggering the formation of lamellipodia that initiate directional migration of mammalian cells is binding of the Wiskott-Aldrich syndrome (WASP)/WASP family verproline-homologous protein 2 (WAVE2) to the actin-related protein 2 and 3 (Arp2/3) complex. This WAVE2-Arp2/3 signal is suggested to be enhanced in some breast cancers, facilitating invasion, and/or metastasis. Here, we demonstrated one cause of the enhanced signal using four breast cancer cell lines (SKBR3, AU565, MCF7, and MDA-MB-231). The WAVE2-Arp2/3 signal was estimated semi-quantitatively by counting the number of lamellipodia expressing both WAVE2 and Arp2 using high-power confocal laser microscopy. Higher expression of the WAVE2-Arp2/3 signal was detected in SKBR3 and AU565, which have HER2 gene amplification, than in the other two cell lines that lack HER2 gene amplification. Trastuzumab suppressed both the formation of lamellipodia and migration in a Boyden chamber experiment in SKBR3 and AU565. When the HER2 gene was transfected into MCF7, the number of both lamellipodia and migrated cells was increased. This enhancement of migration did not occur in the presence of extracellular matrix, and zymographic analysis showed no clear difference between HER2 gene-transfected cells and MCF7 cells. Immunohistochemical analysis of 115 cases of breast cancer revealed that coexpression of WAVE2 and Arp2 was significantly correlated with HER2-overexpression (P < 0.0001). These data indicate that an abnormal signal resulting from HER2 gene amplification activates lamellipodia formation in breast cancer cells, which initiates their metalloproteinase-independent migration. © 2011 Springer Science+Business Media, LLC.

Marcos I.S.,University of Salamanca | Moro R.F.,University of Salamanca | Costales I.,University of Salamanca | Basabe P.,University of Salamanca | And 3 more authors.
Tetrahedron | Year: 2013

Biomimetic synthesis of 12-epi-ent-pentacyclindole 7, using as key step the cyclization of 12-epi-ent-polyalthenol acetate has been carried out. This way, the structure and absolute configuration of the natural product pentacyclindole 1 has been confirmed. The synthesized indole sesquiterpenes 7, 11 and 12 show cellular proliferation inhibition of a number of human leukaemic and solid tumour cell lines. © 2013 Elsevier Ltd. All rights reserved.

Rivero D.,University of Florence | Herrero S.,Karlsruhe Institute of Technology | Moreno S.,Institute Biologia Molecular Y Celular del Cancer
Eukaryotic Cell | Year: 2010

The mitogen-activated protein kinase (MAPK) Sty1 is essential for the regulation of transcriptional responses that promote cell survival in response to different types of environmental stimuli in Schizosaccharomyces pombe. In fission yeast, three distinct eukaryotic initiation factor 2α (eIF2) kinases, two mammalian HRI-related protein kinases (Hri1 and Hri2) and the Gcn2 ortholog, regulate protein synthesis in response to cellular stress conditions. In this study, we demonstrate that both Hri1 and Hri2 exhibited an autokinase activity, specifically phosphorylated eIF2α, and functionally replaced the endogenous Saccharomyces cerevisiae Gcn2. We further show that Gcn2, but not Hri1 or Hri2, is activated early after exposure to hydrogen peroxide and methyl methanesulfonate (MMS). Cells lacking Gcn2 exhibit a later activation of Hri2. The activated MAPK Sty1 negatively regulates Gcn2 and Hri2 activities under oxidative stress but not in response to MMS. In contrast, Hri2 is the primary activated eIF2α kinase in response to heat shock. In this case, the activation of Sty1 appears to be transitory and does not contribute to the modulation of the eIF2α kinase stress pathway. In strains lacking Hri2, a type 2A protein phosphatase is activated soon after heat shock to reduce eIF2α phosphorylation. Finally, the MAPK Sty1, but not the eIF2α kinases, is essential for survival upon oxidative stress or heat shock, but not upon MMS treatment. These findings point to a regulatory coordination between the Sty1 MAPK and eIF2α kinase pathways for a particular range of stress responses. © 2010, American Society for Microbiology.

Cen-Pacheco F.,University of La Laguna | Villa-Pulgarin J.A.,Institute Biologia Molecular Y Celular del Cancer | Villa-Pulgarin J.A.,University of Salamanca | Mollinedo F.,Institute Biologia Molecular Y Celular del Cancer | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2011

Three new polyether squalene derivatives 15-dehydroxythyrsenol A (2), prethyrsenol A (3) and 13-hydroxyprethyrsenol A (4) have been isolated from the red alga Laurencia viridis. Their structures were determined through the interpretation of NMR spectroscopic data and chemical correlations. In addition, four semi-synthetic compounds modulating the solubility of the lead compound dehydrothyrsiferol (1) were prepared without loss of activity. The cytotoxicity of the new compounds exhibited low μM activities. In order to explain their biological properties, docking simulations of the natural and synthetic compounds onto the αvβ3 integrin binding region were carried out. © 2011 Elsevier Masson SAS. All rights reserved.

Caburet S.,University Paris Diderot | Arboleda V.A.,University of California at Los Angeles | Llano E.,University of Salamanca | Llano E.,Institute Biologia Molecular Y Celular del Cancer | And 12 more authors.
New England Journal of Medicine | Year: 2014

Premature ovarian failure is a major cause of female infertility. The genetic causes of this disorder remain unknown in most patients. Using whole-exome sequence analysis of a large consanguineous family with inherited premature ovarian failure, we identified a homozygous 1-bp deletion inducing a frameshift mutation in STAG3 on chromosome 7. STAG3 encodes a meiosis-specific subunit of the cohesin ring, which ensures correct sister chromatid cohesion. Female mice devoid of Stag3 are sterile, and their fetal oocytes are arrested at early prophase I, leading to oocyte depletion at 1 week of age. Copyright © 2014 Massachusetts Medical Society.

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