High Levels of Receptor Tyrosine Kinases in CCM3-Deficient Cells Increase Their Susceptibility to Tyrosine Kinase Inhibition

Cerebral cavernous malformations (CCMs) are vascular malformations that can be the result of the deficiency of one of the CCM genes. Their only present treatment is surgical removal, which is not always possible, and an alternative pharmacological strategy to eliminate them is actively sought. We have studied the effect of the lack of one of the CCM genes, CCM3, in endothelial and non-endothelial cells. By comparing protein expression in control and CCM3-silenced cells, we found that the levels of the Epidermal Growth Factor Receptor (EGFR) are higher in CCM3-deficient cells, which adds to the known upregulation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in these cells. Whereas VEGFR2 is upregulated at the mRNA level, EGFR has a prolonged half-life. Inhibition of EGFR family members in CCM3-deficient cells does not revert the known cellular effects of lack of CCM genes, but it induces significantly more apoptosis in CCM3-deficient cells than in control cells. We propose that the susceptibility to tyrosine kinase inhibitors of CCM3-deficient cells can be harnessed to kill the abnormal cells of these lesions and thus treat CCMs pharmacologically

New data on Polyplacophora from Tuscan Archipelago. I. Leptochiton sarsi Kaas, 1981 and Leptochiton pepezamorai Carmona Zalvide, Urgorri & Garcia, 2004, two species new to the Mediterranean Sea Italian

Two Atlantic species of Leptochiton, L. sarsi and L. pepezamorai, were found in the Tuscan Archipelago, at the St. Lucia\u2019s Bank. This area between the Corsica and the Gorgona Island is characterized by extensive white corals and hard bottom biocenosis extending from 125 to 800 m, which is particularly rich in molluscs. The two species were found looking over a great amount of old detritus from a depth estimated near 500 m. The study of L. sarsi (compared with some Atlantic specimens) permit us to better define some morphological features of this species, not well characterized in the original description. The collection of these Atlantic species in the Mediterranean Sea extend to 34 the number of species of Polyplacophora present in this area

A new species of Leptochiton (Polyplacophora: Leptochitonidae) from the Southwestern Atlantic

Leptochiton sanmatiensis, new species, is described from shallow-waters of northern Argentina. The species is characterized by having a quincuncial arrangement of tegmental granules on head valve, lateral areas of intermediate valves and postmucronal area of tail valve, and a longitudinal arrangement of these structures on the central areas of intermediate valves; each granule having a macraesthete and four micraesthetes. In addition, the new species has pectinated dorsal scales, with 14-21 ridges; a low number of ctenidia (up to six on each side in the largest specimens); and the second lateral tooth with three denticles in the cusp. The species lives on small gravel and shells.Fil: Güller, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales ; ArgentinaFil: Liuzzi, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales ; ArgentinaFil: Zelaya, Diego Gabriel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Biodiversidad y Biología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

BAG-1, a negative regulator of Hsp70 chaperone activity, uncouples nucleotide hydrolysis from substrate release.

Molecular chaperones influence the process of protein folding and, under conditions of stress, recognize non-native proteins to ensure that misfolded proteins neither appear nor accumulate. BAG-1, identified as an Hsp70 associated protein, was shown to have the unique properties of a negative regulator of Hsp70. Here, we demonstrate that BAG-1 inhibits the in vitro protein refolding activity of Hsp70 by forming stable ternary complexes with non-native substrates that do not release even in the presence of nucleotide and the co-chaperone, Hdj-1. However, the substrate in the BAG-1-containing ternary complex does not aggregate and remains in a soluble intermediate folded state, indistinguishable from the refolding-competent substrate-Hsp70 complex. BAG-1 neither inhibits the Hsp70 ATPase, nor has the properties of a nucleotide exchange factor; instead, it stimulates ATPase activity, similar to that observed for Hdj-1, but with opposite consequences. In the presence of BAG-1, the conformation of Hsp70 is altered such that the substrate binding domain becomes less accessible to protease digestion, even in the presence of nucleotide and Hdj-1. These results suggest a mechanistic basis for BAG-1 as a negative regulator of the Hsp70-Hdj-1 chaperone cycle